Neurotransmitters: The Inflamed Brain

Hello everyone, and welcome to our summer mini-series. I don't know about you, but I love the title. I didn't come up with it; my marketing person did. It just sounds happy. Considering what's going on in this world, we could all use a little happiness, I think.

So, we are in our summer miniseries, and it's our most popular miniseries that we've ever done. So, I'm, I'm welcoming you back. If you're new, then just welcome to being here. I'm Dan Kalish. Who am I? That is me. I have been doing functional medicine for a long time. I am on the faculty of the IFM Practice Implementation Program. In fact, I am the program. They centered the whole thing around me, which is a compliment. I will take very kindly. Worked with the Mayo Clinic. I've done a lot of stuff.

Really, what's happening out? The most exciting thing is I'm recording a new class. We have Dr. Richard Lord. So, I have moved from being the guy that's teaching to being the producer, and I'm producing a class with Richard, who, if you don't know Richard, is the, he's the leading scientist in our entire industry, right? He's the, the scientist that developed the GI Effects test and organic acids. It was all his idea, and he's from his way. I became most of what we now do in functional medicine. And so, Richard and I have been working together for the last three years, and I don't know, we have a great time together. He's a genius. He created our lab-based field, and now we'll have a course that I'm going to be releasing on his work, basically in his voice, in the fall. So, I've been working on that two, three days a week with Richard, and it's just been an amazing experience. And, you know, Richard and I teamed up together because he's the brilliant scientist, and I'm like the guy that actually does the work every day. I'm still in practice. I still see patients. Everybody, well, not every day, but twice a week, and you're still trying to sort this out from a clinical standpoint, which is what tonight is all about.

And so, also, if you're interested in this class and you like it, we have a master class that's more detailed. It's $49, and it goes into more depth about the neurotransmitters. So, if you like what you're hearing today, you can sign up for this thing as well, and we'll send out links to the sign-up thing, so you don't worry about trying to write that down. It's kind of confusing, anyways. Doesn't. So, yeah, we'll send out links of that, but you guys are interested, you can do the master class later for some more detail.

So, um, you know, one thing I wanted to cover today is how to really get the brain chemistry / lab test / do I use tryptophan, tyrosine, 5-HTP, mucuna? How all that works on the backend clinically, and then talk about inflammation and, you know, how you can identify inflammation on the labs. And we'll show a whole bunch of labs in a few minutes so you guys can see how to actually do this for real. And, you know, there's a couple of different patterns that you'll see, and we can talk about the low dopamine patient and how that relates to mycotoxin exposure and sulfur amino acids. Then also talk a little bit about the low serotonin patient and how that relates to chronic inflammation and whatnot. And we're going to keep it brief, so I'm going to zip through the slides pretty fast so we can look at some labs, you can guys can see some examples.

But a big-picture part of all this is that there's different reasons why this happens that we're not getting into detail on, but, um, transit and just straight-up deficiency states. People are stressed, they don't eat well. They have, I had a patient like this today. She just has a chronic GI malabsorption problem. Let's master brain drug depletion, whether it's an SSRI or cocaine. If you're long-term recreational prescription drug use, that will deplete these chemicals every single time. There could be damage to the neurons from physical trauma, head injuries. It could be damage from environmental toxin exposure. If we see that all the time as well, as it is. And then there's the huge and looming genetic factors, which you can also see on these labs if you know how to interpret them properly. You can see the people that have genetic problems as well, which is super cool. And you can, in fact, find all these different types. You can differentiate between a stress neurotransmitter problem or an environmental toxin exposure problem or a genetic problem. As you learn how to read the, read these labs at a deeper level, you can put all these things together, and it's really clear, crystal clear when you can do that.

And then, and from a patient experience, people get overweight, they get tired, they're depressed, they have weird things with food going on, binge, they have anxiety attacks, they can't wait, they're in pain all the time, they have headaches. It can, you know, all the way through to Parkinson's. So, there's all kinds of, you know, experiences that people have when these brain problems get, get going. But it certainly doesn't feel good. The most common things I see are tired, overweight, digestive issues, these kinds of things.

So, I wanted to go, kind of go backwards. Usually, I talk about the supplements at the end, but for those of you that might not last the whole 40 minutes, let's talk about the supplements at the beginning, just in case you care. Okay? So, and this is like the biggest conundrum, like why would you use tryptophan? Why would you use 5-HTP? Why would you use tyrosine? Where we use mucuna? And then what are the key cofactors? None of this will work if you don't have enough B6. None of this will work if you don't have enough, that's all four compounds. None of this will work if you don't have a full eight. So, you can't just use amino acids by themselves. You have to give the, the nutrients that help people use the amino acids, or it would be like hanging, you know, it'd be like someone was hungry, like if your kid, and came into the kitchen, like your kid came into the kitchen was like, "I'm hungry, I want some cookies," and you handed them a bag of flour. You know, you say, "Well, here, eat this." And the kid looks at you like, "Well, you're crazy. You don't have to eat flour." There's no, you have to make the cookie, right? So, in order for tryptophan to work or 5-HTP to work, you have to have the B6, or it's completely useless. It's like a bag of flour would be to a kid that wants a cookie. It's just not, you have to assemble this thing, right? And to assemble, you need the B vitamins.

So, I'm going to focus today, though, primarily on inflammation and the kynurenine pathway because I think that's something that's complicated and hard to understand. And I think when I finally understood it, it just opened up this whole new world of depth of ability to treat brain conditions. Pretty profound experience that I had in the last couple of years learning how to do that. And talk about how the kynurenine pathway can, for tryptophan, it grabs tryptophan away, and it causes this whole big problem with glutamate that we're going to look at in a few minutes. And we also want to, probably not going to get into the amino acids, but we're going to try to keep it to a shorter talk today. But to start off with the punchline, if you've ever, you know, been an hour around academic circles, I grew up in Berkeley, California. It's like the most academic town you could ever get. Pretty much every single kid that I grew up with, their parents were professors at Cal Berkeley. And so, like, the way that academics do stuff is really kind of funny. Is it, they, they do talks, and then they'll build and build and build to a conclusion, and then they tell you the punchline at the very end, once they build this argument. And understand that's a great way to learn for academic reasons. But when you're learning to try to, you're trying to learn how to do something and try to acquire skills, if you want to have, like, a really clear definition of what you're trying to figure out, what's the end result of this talk? You should know how to use tryptophan to 5-HTP, and which one way, right? You should be able to find patients who have inflammation in their brain looking at the lab. And so, I'm going to start with the products and start, kind of start with the punchline first. Why would you use tryptophan? Why would you use 5-HTP? And how does that relate to inflammation?

So, tryptophan is an essential amino acid. Tryptophan is responsible for the production of all proteins in the body except for collagen. So, if you do not have tryptophan, you cannot, you cannot assemble a protein. Let's just forget about the brain for a moment. If you don't have tryptophan in your system, this is true for all living beings. It's not just human beings, it's all life on planet Earth. If you don't have tryptophan, you can't, there's probably some bacterial exceptions, but they say all mammals for sure. If you don't have tryptophan, you can't assemble a protein. And the major role of tryptophan, look at this, 90% of it, right, is going to help assemble proteins. It's a very, very important thing because these proteins are what make our bodies work. It could be a heart muscle, um, it could be a heart cell, or it could be a muscle cell, or it could be a bone protein. It could be an enzyme. It could be anything that you're trying to make from amino acids. If you don't have tryptophan, you can't assemble it. So, in addition to that, tryptophan also converts into 5-HTP, which is how we make serotonin. But one of the things when I was learning how to do this work, I always just thought of tryptophan as a serotonin precursor and maybe a melatonin precursor. Never really thought about the roles of tryptophan. Believe it or not, there's like whole journals dedicated to this when you get really into it. The International Journal of Tryptophan Research. I don't know, it sounds kind of sketchy to me, but there's actually a group of people that they just think about this and write articles about this.

So, let's look at this article from the International Journal of Tryptophan Research. So, number one, I just want to highlight the most important part. The role, the principal role of tryptophan in the human body is as a constituent of protein synthesis. That's a big statement. We're also going to look at how it relates to kynurenine or kynurenic acid and serotonin. But just remember that when you use tryptophan, you're going to encourage the growth and ability to make all proteins. That's every enzyme, that's every neurochemical, that's every hormone, that's every, everything. So, tryptophan is a major player. What does it mostly do? It mostly plays a role in protein synthesis, and that's its most important role. Also, tonight we're going to talk about kynurenine and serotonin, but don't want to forget the bigger picture here. Oh, and that's too complicated. I want to look at that right now.

So, why would you use 5-HTP when tryptophan has this amazing ability to heal all body tissues? Where there may be some times when you don't want to use tryptophan, and to get the serotonin balanced, you want to use 5-HTP. And here's the reason why. So, serotonin, when serotonin levels go up, and serotonin levels go up, there's a little signal that your body sends over this tryptophan hydroxylase enzyme, and it tells that enzyme to just stop converting tryptophan to 5-HTP. So, let me say that again. If your serotonin levels go up to a certain point, there's a shutoff valve here, and this little signal goes over to your tryptophan hydroxylase enzyme, right? And it says, "Okay, gang, stop. No more tryptophan going to 5-HTP. We got enough over here. Stop already. Stop already." What are you going to do with all that tryptophan? You're going to make all these other proteins here, right? Every other body protein except for collagen. There's plenty of things for tryptophan to do out there, and only a very small percentage of it is needed for your brain. So, in other words, if you give somebody tryptophan, at a certain point, the serotonin levels will not continue to go up. 5-HTP has passed that enzyme step. So, 5-HTP will convert over to serotonin as, as much as you give the 5-HTP. So, if you only want serotonin to be impacted, 5-HTP is better. If you're not getting the benefit you need from the tryptophan, you may need more serotonin in the system, in which case you may need to give more 5-HTP and not do tryptophan in some cases. You can use both. So, tryptophan is better from a global perspective. 5-HTP is better from a perspective of just wanting to only get serotonin levels up. So, you can use either if they're interchangeable, okay, in some ways. If you understand that one does everything, the other just focuses on serotonin. One can get serotonin up to a limited degree, the other can get serotonin up, you know, higher. They may be, you know, required for some people. Okay? So, just, that's something to keep in the back of your mind. That's the same thing. That's a reminder to take the class.

Okay, this is alright. There's now this get into inflammation a little bit. So, inflammation effects on brain glutamate. And I think this is really interesting, and this is where I'll show in the labs how all this works. So, when you're inflamed, when the body is inflamed, and the brain becomes inflamed, all these complicated things happen. And one of them is a production of all these cytokines. And in the process of doing all this inflammation and responding to all these inflammatory issues, one of the big things that happens is that your body starts to make kynurenine, and then quinolinic acid out of L-tryptophan. And there's an enzyme involved in all this. Let's see if I can make that a little bigger so you can see it better. Can I? Oh, yeah. There. Look at me. I just did that. So, again, when your body's and when your brain is inflamed, and that inflammation could be coming from an infection in the gut, it could be coming from somewhere, neurotoxin, could be coming from a head injury, right? When your brain is inflamed, whatever may be inflaming it, we're not talking about the source of inflammation right now. Tryptophan, through the IDO enzyme system, gets converted into kynurenine, and then to quinolinic acid. And we're going to measure these on the lab. I'll show you that in a second. Once that quinolinic acid gets up and rolling, and again, this is due to neuroinflammation, it does something quite evil. It goes over to the L-glutamate system, which is the majority of your excitatory neurotransmitters, right? L-glutamate, and it excites this system. It just pushes it to the brink. And when it gets overly excited, these NMDA receptors go kind of crazy. Things go bad, right? People get really severe symptoms of anxiety or depression, or you think of all the things that happens when your brain gets this overly agitated. It's a very negative situation. And this is all resulting from inflammation driving kynurenine and quinolinic acid.

So, we're going to show you how to measure kynurenine and quinolinic acid on the labs and see if there's inflammatory processes happening. If it is happening, you can use things like magnesium to calm it down. You can use any kind of anti-inflammatory to balance this out and start to look at the other brain markers and put together a program to really treat and heal the inflamed brain. But bottom line is, if the brain is inflamed, this L-glutamate system gets out of control, and you have over-excitation. These neurons get, it's like, imagine like a water balloon getting jiggled too hard, then they burst. And you remember this whole, like, influx of calcium and all that stuff that just goes ballistic, and it causes damage to the brain itself. And then, of course, it doesn't feel very good.

So, let me just show you real quick what a lab looks like to test this and get some grounding in all this. Just see here. Here's one. So, this is an organic acids profile from Genova Lab. There you go. And I just want to show you the markers here. Again, organic acids, organic acids profile from Genova Lab. And you'll see here's your kynurenine and quinolinic acid right there. These are the neuroinflammatory markers right here. You can see in this particular patient, kynurenine is quite high. That's bad. That means there's neuroinflammation. But the quinolinic acid is quite low. That's not good. How could that happen? That's extra bad. They should, you know, if the brain is inflamed, you would think they would both be high. If kynurenine is high and quinolinic acid is low, it's an even worse situation. Those people are even more depressed and more anxious, more exhausted than the regular folks that have this problem. Okay? So, anyways, that's the lab-based. And just so you can see on the pathway, is the labs that we're measuring here, kynurenine and quinolinic acid. Kynurenine is produced from tryptophan. So, every molecule of kynurenine you make in response to inflammation, you're making all these inflammatory agents, you're making these cytokines, right? In response to that, cytokines, that's a buzzword now, yeah. In response to that, you're losing out on the ability to produce serotonin. Every molecule of these inflammatory cytokines you make is a molecule of serotonin you can't make. So, serotonin levels are dropping as this is happening. And quinolinic acid is stimulating and agitating the brain. So, imagine this, your patient's serotonin levels are plummeting, and their excitatory bad stuff is accelerating. It's like this kind of vicious double whammy. That's the inflammation response in the brain.

Now, there's one other kind of like punchline here, which is that kynurenine also exists in your liver. And so, when you're measuring kynurenine, you can't tell whether it came from the liver or the brain. You, so you have to be able to differentiate. And this is like, I know this sounds kind of abstract, but if you understand this concept, you will totally be able to help so many people. So, it's an obscure, kind of sounding thing, but it has profound clinical ramifications once you learn how to do this. I wouldn't be talking about it if it was like, really profound. So, I just want to point out that tryptophan in your liver, now we're in the liver, also gets converted into kynurenine. Okay? Also gets converted into kynurenine in the liver. It's a whole separate pathway. It's this weird thing where your liver is taking tryptophan and converting it into vitamin B3, of all things. So, this is happening separately in your liver. And when you're looking at the labs, you have to learn how to distinguish, is this level high? Is this kynurenine high because of brain inflammation? Is this kynurenine level high because there's something going on in the liver? And then the liver, if it's high, it's a B6 deficiency. In the brain, if it's high, it's a neuroinflammatory disorder. So, you need to be able to differentially diagnose these two.

So, now, another way of looking at this, it's the same thing here, but we'll look at it from a different angle. Quinolinic acid impacting glutamatergic neurons. So, again, we have our quinolinic acid. Remember, we had the kynurenine. Wait, wait. Here we have tryptophan. The brain is inflamed. You're making these cytokines. Now you've got your kynurenine. Now you've got your quinolinic acid. That quinolinic acid is sneaking in here and it's causing all kinds of problems with this glutamate system. The glutamatergic neurons are getting messed up, and these are a very important, very primary system of neurochemicals and neurons in the brain. Okay? And there's lots of stuff you can read about this, but I thought this article was pretty interesting. Yeah, anyway, it's about, what do I need to read about all these articles? But anyways, you should read about these things because it's pretty interesting and it kind of helps you fill in, I think, the pathways and your understanding of what's happening with your patients. But I think here we go. This pathway here, here, and this is not some like alternative medicine idea. This is like basic science. Here we go. Since this way, the kynurenine pathway of tryptophan metabolism is induced, is induced, is stimulated, right? By immune activation and stress. By immune activation and stress. Immune activation and stress. So, the immune system is under, you know, attack. You go gut infection, you're going to have this pushing of the system. And then here's the interesting thing about that. Again, this British Medical Journal article. Increasing kynurenine levels in the brain produces behavioral and cognitive changes to those encountered in psychiatric conditions. That sounds familiar, right? People get a little weirded out when they have that kynurenine go up. And it says, like, "Oh," and then this is another aspect of this study. I was just great. And this is like basic medical journal stuff. It's not like far-out hippie stuff, right? The relationship between kynurenine and immune function may have wide relevance to sickness behavior. This is what we see all the time. People are tired, and they're depressed, and they've got chronic gut infections, all this happening, you know, having this direct impact on the brain.

Okay, so let me show you. I'm going to skip around a little bit here and show you a few other things that are going to be important. So much to talk about, but this is like a three-hour lecture. We're just going to cover the details here for today. Well, you know what? I don't have a slide or so. Let me just show you on the lab here. So, now, when you're looking at this, so now you've got this idea, right? You've got tryptophan under sort when, when the body is inflamed and the brain is inflamed, your tryptophan is getting diverted to kynurenine production. So, oh, oh, you know what? Let me show you that. The slide is in here. I was in the beginning and I skipped over it. Let me just show you this one. I know I'm skipping around, sorry about that, but you need to see this one. Now, here we go. So, what we're talking about is a patient who's got a lot of inflammation, and the tryptophan is going down to kynurenine, and then that's going to quinolinic acid, and then you're getting all these bad neurodegenerative, neuroinflammatory reactions. What's not happening is that tryptophan is not going over to 5-HTP, and it is not going over to serotonin. So, again, every molecule that sneaks down this kynurenine pathway is not going to serotonin. So, serotonin levels are plummeting, inflammation is skyrocketing, and in addition, you're not even making protein. So, there's a bunch of other things that are going wrong. So, now, when you look at these labs, if your kynurenine is going up, by implication, the serotonin is not doing well. And the quinolinic acid is up, then you know that there's a lot of inflammation going on that's directly impacting your brain or the brain.

So, let me show you some example labs. So, we saw this one a minute ago. Let me skip into another one so you get more familiar. Again, these are organic acids profiles from Genova Lab, and they're pretty straightforward. Organic acids profile. They cost maybe, I don't know, maybe $300 for patients to do. It's absolutely worth every penny of it. Would not question the price at all. Okay. Okay, that's the only one there. Hang on. Let me find everyone here. We go. Here. So, here's another lab. Same lab, organic acids profile. And look, kynurenine and quinolinic acid. They're both high. So, what do you know right away? There's inflammation impacting the brain. Serotonin levels are plummeting. Quinolinic acid is up, so there's this agitation, over-excitation happening in that glutamate system. So, right off the bat, you know serotonin is not doing well. That's plummeting. Depression, anxiety, sleep problems from that. Glutamate is getting overly done. Anxiety, depression, other problems from that, right? So, on both sides, things are going poorly. So, then there's a bigger picture solution here, which is try to find the source of inflammation and all that. But in the short term, you also just want to be able to then treat these. And that's it.

I'll tie in one more concept because this is, I know, a little confusing, but if you get this part, then this whole thing comes full circle. So, remember we said that this is kynurenine and quinolinic acid is happening in the brain. Quinolinic acid is limited to the brain only. So, if you see high quinolinic acid, it's a brain problem. You don't have to question it. It's always a brain problem. However, as I mentioned earlier, what's really tricky about this is if kynurenine is high, remember your body is making kynurenine in the liver too. And so, a high kynurenine could be a liver problem, or it could be a brain problem. How are you going to tell? And you don't want to miss this one up. This is really important because if you tell somebody they have neuroinflammation, then you're going to treat the neuroinflammation, and you're going to do all kinds of things with tryptophan and B6 and fix their depression and all this stuff, and you're wrong. That would be embarrassing and bad. You want to be sure that it's not the liver version. And the way that you can tell, and this is easy, is you go up to marker 18, xanthurenic acid, and it's a B6 marker. If this marker is high, then they have a major deficiency of B6, and that means that part of the kynurenine problem is coming from a B6 deficiency. And this gets kind of doubly tricky, but when you ever you see kynurenine, check xanthurenic acid. And in this case, you'll see this person has a B6 problem and a kynurenine problem. So, you want to treat both. You give them B6 to clear up the liver issue, and then you can use the things that you would do for brain and repair, magnesium, tryptophan, all that good stuff.

Let me just show you another example or two because once you figure this out, it'll, it'll seem easy. I know it, when I first was learning this, I was overwhelmed and confused for several years, to be honest. So, here's another example, and we see the kynurenine is high. So, we know there's some neuroinflammation. But then we're wondering, how much of that is coming from B6? And xanthurenic acid is also high. So, these are people where you extra, extra, extra special have to give a hundred or two hundred milligrams of B6. Okay? Yeah, in addition to doing the tryptophan and 5-HTP to try to get their brain working, you also want to give a hundred, maybe up to two hundred milligrams of B6 to clear out that xanthurenic acid and to fix the portion of the kynurenine that's coming from the B6 problem, as well as addressing that portion of it's coming from the inflammation. So, again, kynurenine means two things. It can mean that there's inflammation in the brain. It can mean if there's a B6 deficiency. Cover your bases. You check that B6 marker. If you get confused, just give B6. Really. If you get confused, just B6.

Now, an example of where you could really go wrong, and this would be embarrassing. Okay? So, kynurenine is high. Not that quinolinic acid is not high. That's a little suspicious because they should be high together. So, then we're thinking, hmm, is this person experiencing neuroinflammation? I don't know. Let me look at my B6 marker up here. Xanthurenic acid. Is it high? It is. Oh, my gosh. This is not neuroinflammation. This is just somebody with a B6 problem. There's so many levels of understanding to this that I know this is a little confusing, but at least to raise the question in your mind. Next time you see a high kynurenine, check the B6 marker. If it's also high, you're thinking, okay, they have a B6 problem. And in this case, the other inflammatory markers are not high. So, this person just needs B6. They don't have neuroinflammation. And it just gives you this in-depth way to really understand how to treat these kind of cases that I think is pretty profound.

So, let's look at one more thing here and how this can really come together. Sorry, these are the wrong things. I got a second, and then I'll be, I'm going to wrap it up in about 5-10 minutes, and then we'll leave time for questions. You guys have questions. So, let's look at the second part of this talk about this. So, there's some obvious things that you want to do. One is that you want to reduce the source of inflammation. So, if it's a gut infection or stress or whatever it is that's inflaming the brain, you want to address that. And then separately, if you know that the person's been in this pattern for a long time, and they've really been pumping all their tryptophan over to kynurenine, and you see also there's some other markers that we're not looking at tonight that show that serotonin levels are low. So, let's say you confirm that the serotonin levels are low, kynurenine is just getting pumped out. You can give tryptophan or 5-HTP. You're not going to make this problem worse, necessarily, right? They're running this inflammatory pathway not because they have too much tryptophan, they're running it because they're inflamed. So, giving tryptophan or 5-HTP to someone in this situation, assuming that you're dealing with the inflammation, is going to help. Now, if you're promoting inflammation, and probably could make them worse, but we're obviously not doing that. So, we're using adrenal programs or gut programs to reduce the inflammation. Then you can safely give either the 5-HTP or tryptophan to supply the person with serotonin because it's all getting diverted over to this other pathway. Now, what a lot of people do to avoid any potential problem with tryptophan because there's a concern that you might give tryptophan and that we might make this worse. If you're worried about that, just use 5-HTP because 5-HTP can't go down this pathway. So, it's another way to be extra safe. And that's another reason why you might use 5-HTP over tryptophan if you're nervous about the tryptophan making the inflammatory problem worse. Just use 5-HTP. And then remember, we also want to calm down this whole system here, and you can use things like magnesium to help calm down the L-glutamate over-excitation.

Alright, so let me show you a couple of programs and let's see here. I don't know, that's probably enough on the detail stuff. There's all these other slides, but we don't have time for. But just quick reminder, if you guys are really interested in this stuff, I have a neurotransmitter and mitochondrial master class. You can sign up for. We'll be sending you out links here for you. If you want it, it's $49, and it goes into all the stuff in a lot more detail. But that's just, like, one program before we wrap up. And let me show you an easy lab here. It's going to expand so you can see. So, this is one of my more depressed patients. I want to show you the easy part of it, not the hard part. So, let me scoot over this side here. Yeah, here we go. That's easy, right? So, now we're looking at the neurotransmitter markers. Now, this woman is extremely anxious, extremely depressed, depressed all the time, and only anxious in the afternoon and evening. She wakes up not. Anyways, that's a whole thing. She wakes up not anxious. Okay? And now we're looking at her neuroinflammatory markers here. Kynurenine and quinolinic acid in particular are both extremely high. So, we know there's neuroinflammation going on. Then we want to track down where it's coming from. Get the gut working, get the neurotoxins under control, do all that kind of stuff. And then you can decide if you feel like her tryptophan, like giving her tryptophan, is appropriate. You can do that. If you're nervous about the tryptophan because you want to make the inflammation worse, you can use 5-HTP, assuming that she's got all the symptoms of serotonin depletion. Let me see if I can find one more example here for a rat bug. We saw that one already, I think. Let me go back here. I find a new one. One of the things I think helps a lot, at least certainly did with me, and is just to see a high volume of tests, so you start to get more and more familiar with them. And we're obviously just focusing on one little part of this lab, but it's a pretty important part. Oh, here's something happy. So, here's a good one. So, this person has normal kynurenine and normal quinolinic acid. End of story. No brain inflammation. No kynurenine elevation. No quinolinic acid. No brain inflammation. Is their brain great? No. Homovanillic acid is so low that the lab couldn't detect it. DL, means underneath the detected limit. And they can measure homovanillic acid pretty low. If they couldn't find it, this person is really low in dopamine. So, you now know you've ruled out, and this is like a big deal. Now you don't have to worry about neuroinflammation. This depressed patient has severely depressed levels of dopamine, but no neuroinflammation. That takes a lot of pressure off of you. You don't have to go hunting for all these inflammatory problems. You have to worry about all this other stuff. You can just focus on getting the dopamine levels back up. That's something like tyrosine and mucuna to normalize.

So, anyways, I feel like it's a really important way to be able to differentially diagnose people. If you know that they have neuroinflammation, that means a whole different track of inflammatory problem, really. And if you know they don't have neuroinflammation, you can just get to work right away on fixing their brain. And in this person's case, the dopamine levels are extremely low, so you'd want to give them some dopamine support. And I'll end on that thought here. And let me just show you one last thing because I have a slide on this. Talked a little bit about. Make you can use tryptophan for certain reasons. It has this global effect on helping all proteins, production of all proteins. You can use 5-HTP because it's at a later step, it converts more readily into serotonin. You can get serotonin levels up quite a bit higher with 5-HTP. Don't have to worry about it getting caught up in that inflammatory pathway. So, a tyrosine, there's something very similar going on. Tyrosine will bring your dopamine levels up, but there's a shutoff valve here as well. If norepinephrine gets high enough, there's a signal that goes to tyrosine hydroxylase that'll shut down the conversion of tyrosine over to dopamine. So, in other words, you can only bring dopamine up to a certain point with tyrosine. If the tyrosine isn't strong enough to make a difference, and you've tried tyrosine for a month or so, it's not working, then you can use an herbal form of L-DOPA because DOPA, the mucuna product is called, is past that enzymatic step. So, it'll convert it into dopamine as much as you want. It was just the more L-DOPA if you give, the more dopamine conversion you get. And so, again, here's another example, the same thing, but so, sort of, you avoid the bypass, you avoid this shutoff process if you use that. And the, what do you call the non-prescription form, I guess you call it the natural form of L-DOPA is called mucuna. And and mucuna is available from all the major companies that we work with. Again, that could be for, like, the patient I just showed you, a way to get that dopamine level up when they're extremely low. Like, like this is, is this the one? No, this is a different one. Yeah, this is it. This is actually a different one, but they're low and vital mentally. Same solution there. So, if homovanillic acid is low or homovanillic acid is low, either these are low, you can either use tyrosine to start with, or you can use mucuna if you need to give a bigger push. So, again, for serotonin, you can start with tryptophan. If that's not strong enough, you can use 5-HTP. For dopamine, epinephrine, norepinephrine problems, you can start with tyrosine. If that's not strong enough after a few weeks, you can escalate and start to use mucuna.

Alright, so I'm just going to end. Oh, and this is just a random thought, but this is kind of cool. So, in 1918, there was a pandemic, as most of you have probably read about. And right after that pandemic happened, there started to be a small, select group of people who had this really strange neurological condition. They called it, I don't even know how to pronounce it, Von Economo's disease or something like that. So, it seemed to be directly related to the pandemic because it only happened right after the pandemic and then went away. And there is a movie about this if you guys are interested in movies. Awakenings, with Robin Williams, and he plays Oliver Sacks, the neurologist who discovered this problem that was happening. And Robert De Niro plays the patient in it, and he's like frozen, right? He's like the frozen addict examples they have. And he was basically like in a very, very advanced Parkinson's patient, and Vance Lee. And they show this in the movie, and it's a real-life story. Williams, or Oliver Sacks, figured out, "Hey, if we give these people L-DOPA, they come right back to life." Now, of course, I don't want to ruin the movie, but it didn't last very long. But that's the basic idea behind mucuna and why we use mucuna is to, uh, tyrosine because it goes right over to dopamine. Not that I would use that with COVID patients. That's kind of a little aside, but it's just kind of interesting, a little historical thing there.

So, just remember, bouncing serotonin, you may need to get into inflammatory pathways and how to fix them. If you see that kynurenine is high, then you've got to deal with the inflammatory part. If you don't see high kynurenine or high quinolinic acid, then you're off the hook. You don't have to deal with all the inflammatory aspects. You can just fix what you see on the other portions of the neurotransmitter testing. But if you try to treat someone who's got neuroinflammation as if they don't, you know, you're not going to get them getting a little bit better, but not for very long, you know. And it can be frustrating for both you and the patient, too.

Okay, and then if you guys are interested, again, we have this. We have all kinds of things going on with. So, it's, we have a bootcamp that we're starting tomorrow. You can still sign up for it if you want to do the business bootcamp. Let me just show you. We've had a busy summer. This is the busiest I've ever been, to be honest. But here. So, there's the master class, which is super cool. There's also a class we're starting right now this week called the Business Essentials Bootcamp. I've got a really great group of people signed up for that. It's an eight-week class on just business training and financial planning and business planning and all that stuff. It's two months long. It's $4.99 a month for two months. Not too expensive. And we just kind of turbocharged your business over the couple months. So, if your business is kind of lax and ethical, and you want to put some energy into it, sign up for this thing. We're starting this week. And if you want to do one of the master classes, we'll send you out information. That's you.

Alright, so now let me, um, let me just go through questions since they always come up, which is great. And, and I'm sorry to get my screens aligned here. So, much other stuff. Ever heard of the single carbon pool? That's the coolest thing I've learned in a long time. I want to do a whole hour on that at some point. It's this whole methylation. It's the secret to methylation is single carbons. I didn't know that. All right, but the seat. Let me do questions for a few minutes since a lot of questions came in. Let me go back up to the beginning here. Can use the amino acid part of ION to find out nutritional base of neurotransmitter balance? Ooh, that's a good question. Well, looking at amino acids gives you more detailed information, but remember, you could have neuroinflammation, and the amino acids may look okay. So, they're related, but not always going to be connected. But certainly, the amino acids give you another angle on the overall picture. If serotonin builds up too much, I don't know what has happened. It's not that bad, really. People just stop. They'll just complain and just say, "Hey, you know, this, I don't feel very good when I take this." They'll feel nauseous, or their head will feel funny. It'll last for like an hour or two, and you just tell people that stop. So, I always tell people, "Hey, I'm going to give you this 5-HTP. It should only make you feel better." I'll say that like three or four times. "This should only make you feel better. If you have any side effects, just stop. Stop taking it and give me a call." And, you know, you can avoid any kind of serious side effects pretty easily. Hi, aspartic acid to be involved in brain inflammation? That I'm not sure. I've not seen that for. I'm not sure if it's possible or not. Yeah, so there is a measurement of tryptophan on the lab. Yep. See, Tryptophan. So, if you don't, if you want more information than you're getting from an organic acids profile, then the real test, the one that you should all be doing for real, is the ION panel. It's not the easiest thing to interpret, but this is the real deal. Again, it's from Genova Lab. That's an ION panel. It's the granddaddy of all tests, right? It includes amino acids and fatty acids and all kinds of really important things. So, if you want to kind of update it a bit, do the ION panels again from Genova. ION panel. Let's see what test I do for adrenal hormones. Yeah, so I use salivary adrenal hormones. ZRT Labs has them. Doctors Data has them. Thorne has them. Diagnostics has them. Pretty good, easy to get. How do SSRIs affect these pathways? Oh, yeah. So, SSRIs will, over time, decrease the available pool of serotonin. And SSRIs, over time, will deplete available tryptophan. And when SSRIs deplete the available tryptophan, remember that has ramifications for the entire body because tryptophan is a rate-limiting step in the synthesis of all proteins. So, the reality that SSRIs deplete tryptophan can be catastrophic for patients in more ways than you can imagine. Well, there's 20,000 different proteins made by the human body, so there's 20,000 different ways that an SSRI could screw one of your patients up. I'm not against people using those medications for short periods of time, but putting somebody on Lexapro or something like that for the rest of your life is really risky if you don't have the proper nutritional support. So, that's a good question. Let's see. Mucuna. Mucuna is a herbal form of L-DOPA. Most of all the supplement companies will have a mucuna product, usually as mixed in with some tyrosine. And that is probably my favorite supplement of all time. Mucuna. It's so effective because when you find people that are low in dopamine or epinephrine or norepinephrine, and you get their levels up, it's just like night and day. It's probably my favorite supplement. So, if you're not using mucuna yet, yeah, you should definitely use it. And in the way that I just described, you're looking to see if the dopamine markers are low, and then using the mucuna or tyrosine to get all that working. Okay. Oh, yeah, if you have patients that don't want to do a blood draw, just through the organic acids test, or you can do that other one. They have the metabolomic services substitute. So, so Dorinda is asking, "Client with former meth addiction, dopamine extremely low, feels better on mucuna. The highest dosage you can use?" I would just titrate her up to what you feel is the therapeutic dose where she feels is the therapeutic dose where she's hit a plateau in terms of the benefit. Keep her on that for like a week or two, and then grab another test and see what the levels look like when she's doing that. I'm doing ION panel if you can, or at least an organic acids to, you know, test if on lab you see dopamine is low. When you don't have organics, can you start with tyrosine? Absolutely. Yeah, absolutely. Anytime you see low dopamine. Can correcting serotonin also simultaneously correct melatonin? In fact, it should. So, let's, let's look at that pathway. I want to talk about methylation at the end, even though that's not what I'm supposed to be talking about, just because it's so cool. So, if you guys want to stick around for the last couple of minutes, I'll do the methylation thing. All right, here we go. Um, so the question is, here's melatonin. So, if you give tryptophan and you're not inflamed, right? You're, you're fixing their inflammation. You got the mother-in-law to move out of the house, so they're not stressed. You got, you know, the child.

That was an alcoholic to get alpha alcohol so they're not stressed. You got their H pylori infection cleared up so they're not inflamed. Whatever it is you're doing, you stop this inflammatory, horrible nightmare that's happening now.

You're giving tryptophan that converts to 5-HTP. It'll simultaneously bring up serotonin and melatonin, which is part of why it helps people sleep so much. And it's tryptophan better? Well, it's different. Remember, because tryptophan is the rate-limiting step in all protein synthesis. This whole research article is divided into tryptophan. 5-HTP is important, but it has a different, slightly different purpose.

Does the ion panel include the OAT test? Yep, the iron panel has an OAT test in it. Do you do the touch panels? Yep, absolutely do. Do the touch panels? They had one today. So I differentiate. Sometimes they do touch panels, sometimes they do the salivary adrenals. Yeah, we'll send out a link to this tomorrow, probably.

Can you overdose on Mucuna? Absolutely, you can. And to be a little careful with Mucuna, but just tell people as you hand them a bottle or virtually prescribe the bottle, this should only make you feel better. If you have any negative side effects, stop and email the office. And with Mucuna, it's very obvious. They'll take a pill, they'll feel weird and spaced out, like someone's got a wrench in their brain, and they will stop. It'll go away in an hour. You'll never come back. I've done this thousands of times. I've never had a problem, but you gotta warn people. This should only make you feel better. If you have any side effects, stop taking it immediately and email me. You know, if you do that, you won't have problems. So if people take a little bit too much, you just tell them to back off. And honestly, in my practice, it's been two or three years since I OAT'd anybody on Mucuna. So if you're careful when you titrate them up gradually, you won't have too many problems.

When you retest, you can either retest on supplements or off. Usually, I have people stop taking supplements for a few days before.

OAT favorite agents for brain inflammation? I don't know. That's a hard one. Probably curcumin-derived products. They work really well. Of course, magnesium. But you know, curcumin is a great anti-inflammatory, and people seem to react to it really well.

Let's see. How long do you usually give tyrosine? A mechanic, like around six months, something like that.

Okay, now we are formally ending the talk on neurotransmitters, but you can all hang out if you want. I'm going to pause for like three seconds, and I just got to tell you this because this is like the closest thing I've learned in a long time. So we're all kind of obsessed with folate, MTHFR, blah, blah, blah, blah, right? And then we know that folate is super-important, a super-important for methylation, and methylation is required for making epinephrine, norepinephrine, dopamine, serotonin, most of your hormones, most of your detox pathways, everything. And gets required for methylation is kind of required for everything. So a large part of these programs is to give people folate if they need it. Super important.

But here's the cool part. Look at this. Here's, I don't know, some of you guys may already know this, but I didn't know this until a little while ago. It's kind of embarrassing. So here's the whole methylation thing happening. Here's your methionine, and it's going through all these different things, and then it's going into homocysteine. In your body, like, get some B12, and then it turns it into methionine. It's just spinning around in this little cycle here. But that's a pretty important thing to have working. And you need a bunch of these substrates. And then the end products of this are are they important? Well, I don't know how important is like nucleic acids, that's your DNA, right? How important is epinephrine? How important is your detox pathways? These are all like as important as it gets. So methylation, we all know, is like super important.

But what I didn't know until recently is that there's another side to this. Okay? So you've got this whole thing going, and we know here, then you read all about it. You need B12, or the whole thing won't work. You need folate. See where folate shows up here? You have to have folate, or none of this works. Not important. Folate is it? Just shows up everywhere. What's the THF? Tetrahydrofolate. Not important. That is it's like literally everywhere. Okay? So you have to have folate. You have to have B12 for this to work.

But the part that's like mind-numbing is, wait, how does this really work at a deeper level? What is the folate pushing around? So the folate here, your 5-methyl tetrahydrofolate, right? What's it really doing? It's grabbing amino acids: serine, glycine, histidine, glutamate, and tryptophan, specifically. It's grabbing single carbons from those amino acids. Did you guys know that? Does anybody know that? Am I like tripping out here? Raise your hand. Send me a little chat message if you're like, "Yeah, Dan, everybody knows that." Is that like mind-numbing to me? I didn't know that. Why didn't somebody tell me that a long time ago?

So let me say this again. The single carbon pool. The whole point of methylation is you're throwing around these carbons, right? You're throwing them around, you're methylating things. The single carbon pool comes from serine, glycine, histidine, glutamate, and tryptophan. Okay? What is that the ramification of that is that if you don't have serine, glycine, histidine, glutamate, and tryptophan, if you don't have these amino acids, then methylation is just like dead in the water. All right?

Now, why and why is that important? Well, if you show one other thing here is that some of these functions of folate and some of these movements of the single carbons go up to 5-methyl, and then all this methylation stuff happens over here in your liver. And by the way, if you add B12, this whole thing completely falls apart. B12. If lack of B12 means everything just shuts down. But look what else is happening here. You take those single carbons that you're grabbing, and forget about this whole methylation thing up here. Look what happens. They go right over here, and that's how you make DNA and RNA. That's pretty profound. I don't think it gets more profound than that in terms of a product. That's how you make DNA and RNA is from pyrimidines and purines from the single carbon pool that folate's pulling over for you.

So these amino acids then, if you're low in amino acids, this apropos of Jay's question earlier, if you're low in serine or glycine or histidine or tryptophan, for that matter, or glutamate, then this whole thing shuts down. You can't make DNA. You can't methylate. So when you're looking at a lab on my end of this thought, oh, and Susan's kind of smart, she's got that understanding too about methotrexate. So why this, how this manifests on a lab is you can see here is an ion panel. Now, so if you see a patient with low glycine or serine or tryptophan, for that matter, or histidine, low levels, not high, low levels, that means there's not enough single carbons for them to pull over to that single carbon pool. So methylation will just shut down. It's like pulling the gasoline out of a car. You have to have that single carbon pool for that to work.

So anyways, that's just kind of a cool little factoid. It's just another reason to check amino acids if you want methylation to work right. It's not just about B vitamins. So let me just show you one more time, then we wrap up. And I don't know if you ever hit your head against the wall with a methylation patient, you know, and you're like, "Well, I don't know. I'm giving them all these B vitamins. It's helping. They're responding." Maybe they have a mental problem. Well, look again. You have to have the single carbon pool. That has to come from amino acids: serine, glycine, histidine, glutamate, and tryptophan. If you don't have the single carbon pool, you can't do all these other things that involve methylation. Okay? So it's just kind of broadens your understanding. So that when you're thinking about methylation, you're thinking about, yes, but finding homocysteine, B6, B12, and folate. But then you also have to think about where those single carbons are coming from. The patient has to have enough amino acids. So if you have a patient, they're not methylating well, you can't fix it. Test their amino acid levels. And if some of these amino acids are low, like outrageously low histidine and serine and glycine, then you kind of got the problem figured out.

I'm gonna wrap it up for there. Thank you guys for hanging in there and hope you're all having a great whatever time out there, surviving. And we'll have more of these. It's the summer series, so we'll be back in a week with more information for you guys. All right, take care.