This is Dr. Chris Masterjohn of chrismasterjohnphd.com, and you’re listening to Episode 54 of Mastering Nutrition, where we now delve into Part 2 of Nutrition in Neuroscience. This is Mastering Nutrition with Chris Masterjohn. Take control of your health, master the science, and apply it like a pro. Are you ready? Welcome back everybody. This is part two of a four-part series on nutrition in neuroscience. I am your tour guide in a safari through the wild world of the leading textbook in Neuroscience by Purves et.al., published in 2018, the sixth edition, where as your tour guide, I point out all of the stuff relevant to nutrition. In the first part of this series, we talked about the basic function of a neuron and how it transmits information from one place to another and the nutrients needed for that process. In this part, part two, we talk about the neurotransmitters. We talk about glutamate, GABA, and glycine, acetylcholine, the biogenic amines, including the catecholamines, dopamine, norepinephrine, and epinephrine. Other biogenic amines, such as serotonin and histamine. My favorite catecholamine, dopamine. ATP as a neurotransmitter and adenosine. Peptide neurotransmitters, like substance P involved in pain perception, melanocyte stimulating hormone involved in pigmenting your hair, nails, and skin, controlling your sexual libido and your appetite. All of the releasing hormones that control how the hypothalamus communicates to the pituitary to, in turn, control your sexual function, your thyroid function, and your adrenal function. And finally the endocannabinoids, the things that you make from the fats in your food that act eerily similarly to the stuff in marijuana smoke. We talk about the importance of nutrients like vitamin C, copper, zinc, iron, salt, potassium, calcium, and magnesium. We talk about important conditions, like epilepsy, forming memories, getting rid of memories so that you have room for new ones, and so that you don’t subconsciously or consciously remember things that are harmful to you. How these things dictate our focus, our attention, our motivation, our feelings, and our choices. We look at questions like, can glutamate cross the blood-brain barrier? What could explain glutamate sensitivity and negative reactions to MSG if not? How hyperglycemia could be the main thing that causes brain glutamate to spike. How glycine and GABA can lose their inhibitory functions sometimes and become stimulatory neurotransmitters even though they’re supposed to be calming ones. GABA in foods, what foods are rich in it? How GABA supplements can reduce anxiety and can even speed your reaction time when making hard choices under pressure and might even be able to reduce the negative effect of being exposed to the things that you fear most on your immune system. How substances you make from the fats in your food might help decrease fear and anxiety and increase your willingness to venture out of your comfort zone and explore your environment. And the nutrients you might need if you find that your hair is graying, your libido is tanking, your affectionate response to physical intimacy is lackluster, and you find yourself needing to pee a little bit too much. All this and much more after a brief word from my sponsors. This episode is brought to you by Ancestral Supplements. Traditional peoples, Native Americans, and early ancestral healers believe that eating the organs from a healthy animal would strengthen and support the health of the corresponding organ of the individual. For example, the traditional way of treating a person with a weak heart was to feed the person the heart of the healthy animal. Modern science makes sense of this. Heart is uniquely rich in coenzyme Q10, which supports heart health. The importance of eating organs though is much broader than simply matching the organ you eat to the organ you want to nourish. For example, natives of the Arctic had very limited access to plant foods and got their vitamin C from adrenal glands. Vitamin C is important to far more parts of your body than simply your adrenals. In his epic work Nutrition and Physical Degeneration, Weston Price recorded a story of natives who cured blindness using eyeballs, which are very rich in vitamin A. But now that we understand vitamin A, we know that we can get even more vitamin A by eating liver, making liver good for your eyes. Our ancestors made liberal use of organ meats both to be economical and to utilize their healing and nourishing properties. Animals in the wild do the same. Weston Price had also recorded a story of how the zoos in his era were capturing lions, tigers, and leopards, oh my, only to watch them become infertile in captivity. Researchers then observed what the lions did when they killed zebras in the wild. What they did was they went straight for the organs and bone marrow, leaving the muscle meat behind for the birds, but even the birds took what they could of the organs and bone marrow. Price reported that once the zookeeper started feeding the animals organ meats, boom, their fertility returned. The problem I often encountered though is that many people just don’t like eating organ meats. Let’s face it, if you weren’t raised on them, it can be very hard to acquire a taste for them. That is where Ancestral comes in. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organ meats, living collagen, bone marrow, and more. All in the convenience of a gelatin capsule. For more information or to buy any of their products, go to ancestralsupplements.com. Ancestral Supplements. Putting back in what the modern world has left out. This episode is brought to you by Ample. Ample is incredible. 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If calcium has entered the axon terminal to initiate the release of a neurotransmitter into the synaptic cleft from the terminal of one axon, where it can then interact with the receptors on the next neuron, not always but usually at the point of the dendrite, then we must talk about the neurotransmitters. There are over 100 neurotransmitters, and they can be broken down into several categories. Actually we could break them down into two categories: the neuropeptides and the small-molecule neurotransmitters. Neuropeptides are 3 to 36 amino acids. This is smaller than a protein. And the small-molecule neurotransmitters can be further broken down into a few categories. We have amino acids, like glutamate, gamma-aminobutyric acid, or GABA, and glycine. In the second category of small-molecule neurotransmitters, we have biogenic amines, like dopamine, norepinephrine, epinephrine, serotonin, and histamine. And then we have acetylcholine, which kind of doesn’t fit into either of those categories, and we can kind of talk about it on its own. Now, whether any of these act as excitatory or inhibitory is all dependent on context. It depends on which receptors they’re binding to, and it also depends on the ionic environment based on the question of, how much is the chloride outside the cell versus inside, or is that flipped? But we can make several generalizations. So, mainly we can say that glutamate is excitatory. Mainly we can say that GABA and glycine are inhibitory. We can also say that the biogenic amines, the acetylcholine, and ATP, which itself can act as a neurotransmitter, are generally excitatory, and that most of the other neurotransmitters have functions that are too complex to classify as one or the other. So, let’s go through some of the major ones, one by one, and we’ll talk about glutamate first. Nearly all excitatory neurons in the central nervous system, which is the brain and the spinal cord, use glutamate as their excitatory neurotransmitter. That’s more than half of all central nervous system neurons. Glutamate is the most abundant amino acid in the diet. There is free glutamate that is just on its own, as the neurotransmitter would be, that is not bound up in a protein in some foods. But overwhelmingly, you’re getting glutamate by digesting proteins, and you’re getting more glutamate from those proteins than any other individual amino acid most of the time. But it’s generally thought that glutamate can’t cross the blood-brain barrier. So, for the most part, the glutamate that’s inside your brain is going to be synthesized inside the brain. Now, there are probably some exceptions to this. Let’s think for a moment about what the blood-brain barrier actually is, and the word barrier is a little bit misleading because this is a very dynamic multi-layered membrane- and transporter-based interface between the central nervous system and the rest of the body. Barrier is kind of a strong word. So, at the interface of the blood supply to the central nervous system in both the brain and the spinal cord, we have capillaries delivering blood to the brain. And as with all the blood vessels, these capillaries have a lining called the endothelium, so these endothelial cells of the capillaries are the first layer of the blood-brain barrier. Then there’s a basement membrane that completely covers the capillaries, and then finally some of the glial cells called astrocytes have processes that project to the basement membrane and surround it. Each of these layers has control mechanisms of what does and doesn’t get through. Because glutamate is a neurotransmitter, remember for something that has signaling value, to actually have that value, its normal concentration anywhere where it might represent that signal has to be exceedingly low, and so the brain is very concerned everywhere to keep the extracellular concentration of glutamate exceedingly low because it’s outside the cells at, for example, the synaptic cleft, where glutamate will carry out the signal to excite a neuron. So, when you’re at—imagine being inside the brain at the edge of the blood-brain barrier. You have extracellular space where you want to completely clear the glutamate to keep the concentration exceedingly low. So, you have these astrocytes, the glial cells, that have the projections of their feet that cover the capillaries. They are actively clearing glutamate into themselves to keep that glutamate concentration exceedingly low. But then at the level of the capillary endothelial cell, it, too, is playing a role in keeping that glutamate exceedingly low by using sodium from a gradient created by ATP to pump the glutamate out of the brain. In other words, wherever you are in the brain, your first goal is to clear glutamate into where it can be conserved, so the glial cell can clear it, the neuron can reuptake it, because you want to be able to use it again. But whatever you didn’t clear when you’re at the site of the blood-brain barrier, even those cells are playing their role in clearing it, and at the point of the blood-brain barrier, those capillary cells are clearing it by sending it—by taking it up into the endothelial cells and then letting it flow back out into the blood. So, to say that glutamate doesn’t cross the blood-brain barrier is to say that when you have enough sodium, and when you have enough energy production dependent on ATP, and magnesium, and seven B vitamins, and iron, copper, and sulfur, and everything that you need to prevent anemia, it’s saying that under those conditions, glutamate doesn’t in net cross into the brain any faster than it’s being pumped out of the brain. But that also means that there’s a bunch of things that could go wrong with not having that sodium gradient because of not enough sodium, because of not enough ATP energy, et cetera, et cetera. So, there are people out there and a syndrome vaguely characterized of glutamate sensitivity where people react to MSG or to free glutamate caused by the the breakdown of proteins during long or high-pressure cooking or fermentation, where some people don’t tolerate these products, seem to get an excitatory response to it, and it’s presumed that that’s from the glutamate, although the science is iffy because everyone in the scientific world is kind of saying, well, it doesn’t make any sense because glutamate doesn’t cross the blood-brain barrier. So, maybe it does under some conditions involving a breakdown in the electrolyte and energy balance, or maybe due to inflammation because inflammation generally increases the permeability between cells, the leakiness of barriers, and maybe that breakdown of energy metabolism or inflammation—or breakdown of energy metabolism or presence of inflammation might be predisposing someone to allow glutamate into the brain. Another reason why the significance of dietary glutamate for brain glutamate is generally dismissed in the mainstream scientific literature is that even people fed a lot of MSG generally don’t have their blood levels spike, and that’s because much of the glutamate is actually consumed by your intestinal cells, preventing it from spiking it in your blood when you eat it. But let’s come to the the normal situation, which is, your glutamate in your central nervous system is made in your central nervous system. How is that going to occur? Overwhelmingly, glutamate is ultimately made from glucose in the central nervous system. And that’s because the way that you make glutamate is, you have food molecules that generate acetyl CoA during metabolism, and the acetyl CoA enters the citric acid cycle, and one of the steps in the citric acid cycle is to make alpha-ketoglutarate. Although the alpha-ketoglutarate can continue through the citric acid cycle, it can leave the citric acid cycle, and it can be converted into glutamate. In order for the acetyl CoA to enter into the citric acid cycle and generate alpha-ketoglutarate, it had to bind to oxaloacetate. Oxaloacetate can be made from carbohydrate, and it can be made from some amino acids, but it cannot be made from fat. So, under conditions of a normal diet that is not ketogenic, and you’re not fasting, remember, your main fuel for the brain is glucose. You’re going through 120 grams per day. The glucose is abundant, so the glucose will make all the oxaloacetate that you want, allow the citric acid cycle to use the acetyl CoA and generate alpha-ketoglutarate, that will allow the alpha-ketoglutarate to leave the citric acid cycle and generate the glutamate. But imagine that you’re on a ketogenic diet, and your brain consumption of glucose goes down to 25 to 30 grams a day, and the remainder of that energy is running on ketones. Ketones generate acetyl CoA, but they don’t generate oxaloacetate, and so ketones by themselves are not going to give you that alpha-ketoglutarate. You need to have the source of oxaloacetate or one of its precursors to be able to utilize the acetyl CoA from the ketones to generate alpha ketoglutarate. So you really can’t get that alpha-ketoglutarate, even on a ketogenic diet and even during fasting, except to derive the oxaloacetate from glucose or maybe to some extent from amino acids. So, overwhelmingly under almost every conceivable condition, the main source of de novo glutamate, meaning glutamate that wasn’t glutamate before, new glutamate in the brain generally is going to come from glucose. And I find that really interesting because you can imagine then that hyperglycemic spikes could be one of the main things that cause brain glutamate to spike. And the reason I find that really interesting is, apart from the the potential consequences to how you feel when your brain glutamate is spiking when you go hyperglycemic, the reason I find that interesting is that in epilepsy, one of the key drivers of epilepsy is too much glutamate relative to the inhibitory amino acid GABA. And it’s complicated. Sometimes this is because you have too much glutamate. Sometimes it’s because you don’t have enough GABA. Sometimes it’s that you have GABA, and you have normal glutamate, but the GABA isn’t working properly, and I’ll talk about that more when we get to GABA. But at least in some cases, it’s because you have too much glutamate. One of the interesting things about the ketogenic diet is, on the one hand, the ketogenic diet is the one therapy that’s been shown to decrease glutamate and increase GABA in the brain. And it does that through multiple mechanisms that include affecting the enzymes involved in their production and degradation. What’s interesting is that although that could easily explain the ketogenic diet’s effect on epilepsy, two things stand in the way of this interpretation. One is that whenever the studies that have shown its efficacy have looked at the correlation between the level of ketogenesis and the level of reduction in seizures, there is no correlation. And the second issue is that there is an alternative diet that is based on moderate carbohydrate restriction with low-glycemic foods, and it is a little bit ketogenic, but it’s maybe four times less ketogenic than the classic ketogenic diet, so the blood ketone levels are not that high, and the main effect of the diet is to stabilize blood glucose so you don’t have ups and downs in your blood glucose, and that leads me to think that maybe in these people who benefit from the low-glycemic, low-carbohydrate epilepsy diet are people whose hyperglycemic spikes are the thing that’s generating spikes in brain glutamate that initiate those seizures. With that said, glutamate is absolutely necessary and normal, so we don’t want to compromise our production of glutamate under most circumstances. Most of the time, having enough glutamate is what is making your brain work properly, not only in feeling awake and functional, but even in allowing your senses to be perceived. Like, to have vision and to hear things is because of glutamate, so we want the glutamate. We just don’t want ridiculously high levels and inappropriately high levels of it. So, to get that glucose to glutamate, we are taking glucose. Eventually it’s providing the alpha-ketoglutatate in the citric acid cycle. And then we can take that alpha-ketoglutarate, and we need to add nitrogen to it. We can do that in two different ways. In one case, we take the nitrogen from another amino acid, and that requires vitamin B6. In the other case, we take that nitrogen from free ammonia, and that requires niacin, or vitamin B3. In both cases, this is dependent on B vitamins. To move that glutamate in between cells when it is not acting as a neurotransmitter, we are going to convert it to glutamine using ATP and ammonia to make it into glutamine. And then, as needed, we can hydrolyze it— hydrolyze means use water to break it apart—back to glutamate. Probably some portion of the new glutamate in the central nervous system comes from glutamine in your food, but for the most part, we are taking nitrogen as ammonia on and off of the glutamate to go back and forth between glutamate without the extra nitrogen to glutamine with the extra nitrogen as a means of both controlling the amount of glutamate in the brain as a neurotransmitter and controlling the amount of ammonia in the brain, which has to be there to some degree, but too much is very toxic. Once we send glutamate out into the synaptic cleft by taking vesicles of glutamate, having them fused to the membrane, initiated by, remember, that calcium that came in, the glutamate goes out into the synaptic cleft, it does its thing at the neurotransmitters, then it has to be cleared as fast as possible from the synaptic cleft because, again, the value of having a signal depends on that signal normally not being there except when you want it there. So, to clear it really fast, we take it back up into the neuron, or the nearby glial cells take it up, and that requires the excitatory amino acid transporter, or EAAT, which is a sodium-dependent transporter. That transporter is directly structurally connected to a sodium-potassium ATPase that sits right next to it producing the sodium gradient, using the power of ATP to allow that glutamate to be cleared. So, one of the problems of having too much glutamate isn’t just the existence of glutamate in the brain. It’s that it’s hanging out too long the synaptic cleft. You can imagine that any failure of energy metabolism or not having the right electrolytes, in this case sodium and potassium, to be able to properly use energy to clear it. When the glutamate is in the synaptic cleft, it has the opportunity to interact with glutamate receptors. We can divide the glutamate receptors into two main classes: ionotropic glutamate receptors and metabotropic glutamate receptors. The ionotropic glutamate receptors are ion channels. They do their thing by allowing ions to flow through them. The metabotropic receptors do not allow ions to come in. Instead, glutamate binds to them, and then they do something on the other side of the membrane that initiates some cascade that leads to a second messenger system. Remember, second messenger means signal on the outside of the membrane made some other signal on the inside of the membrane do something, and we gave calcium as an example of a second messenger, and there are many others. So, within those, we can further say that there’s—in the metabotropic glutamate receptors, we’ll kind of get them out of the way because ionotropic is mostly what we’ll talk about. So, the metabotropic glutamate receptors, there’s three classes with eight subtypes spread across those three classes. Their actions are very complex and variable, and they can be excitatory or inhibitory, and usually cannot simply be summarized by one or the other. But usually when we’re talking about glutamate, what we’re thinking about is the ionotropic glutamate receptors, and those are the receptors that fulfill glutamate being the primary excitatory neurotransmitter in the central nervous system. Those ionotropic glutamate receptors fall into three classes, each named after specific chemicals that have been used in experiments to stimulate them. There are the AMPA receptors, the NMDA receptors, and the kainate receptors. Of these three, the kainate receptors are the rarest, and the most nuanced, and the least studied. And mostly what the Neuroscience textbook gets into are the AMPA and NMDA receptors. The AMPA receptors mediate the vast bulk of the excitatory effects of glutamate in the brain. The NMDA receptors are usually involved in what’s called coincidence detection, which means being able to pair different signals together and say, oh, that’s happening there, and that’s happening there, well, when they both happen at the same time, I’m going to initiate some special cellular process. Now, all three of these ionotropic receptors, AMPA, NMDA, and kainate, allow sodium and potassium to flow freely through them. And you might say, wait a second, the sodium is going to come in, the potassium is going to go out, is anything in net going to happen? But remember that the sodium gradient is much stronger than the potassium gradient. That’s partly because the sodium-potassium ATPase brings more sodium into the cell— I mean, brings—excuse me, brings more sodium out of the cell than it brings potassium into the cell, but also a portion of that potassium gradient is dissipated by the potassium-chloride transporter that uses the potassium gradient to bring chloride out of the cell. So, to freely allow sodium and potassium to flow is going to have a depolarizing effect because the primary action out of the two is from sodium coming into the cell. So, we can simplify that, and we can say, glutamate acts on these receptors to allow sodium to come into the cell. That takes—the cell had been more negative inside than outside, you bring positive charge from the outside to the inside, you depolarize that cell, you reduce the magnitude of the charge differential, and that excites the neuron. Of these, the NMDA receptor has several unique things about it. So, first of all, the mechanism by which it is closed when it’s closed is that there is a magnesium ion that blocks its ion channel. So, in the polarized or hyperpolarized state, ions such as sodium cannot flow through because the magnesium is in the way. So, what that might imply is that if you don’t have enough magnesium in your diet, the NMDA receptors are never properly closed, and you’re getting effects of glutamate that you shouldn’t be getting because you don’t have the magnesium to allow the NMDA receptor to be properly off. Usually, in order for the magnesium to leave the ion channel and allow the NMDA receptor to be activated, there has to be depolarization of the nearby membrane. And this is what allows the NMDA receptor to act as a so-called coincidence detector because something else has to depolarize the membrane in order for the glutamate to be able to activate the NMDA receptor. So, imagine that there’s no depolorization of the membrane. Glutamate binds to the NMDA receptor. Magnesium’s in the way. Glutamate does nothing to remove the magnesium. Only depolarization to a certain threshold does. Nothing happens. Meanwhile, let’s say that glutamate had activated a sufficient number of AMPA receptors nearby to depolarize the membrane, alongside binding to the NMDA receptor. Glutamate is bound to the NMDA receptor, the depolarization initiated by its binding to the AMPA receptors removes the magnesium. Now the ions can come in, and the NMDA receptor can allow ions to flow through because it had both the coincidence of glutamate binding to it and nearby depolarization from the other signal to remove the magnesium. Now, you might say, wait a second, what’s the NMDA receptor going to do differently than the AMPA receptor? They both allow sodium and potassium to come through. They both depolarize the membrane. Well, then that gets us to the third thing unique about the NMDA receptor, and that is that the NMDA receptor allows calcium to come in, too, and what does calcium do? It acts as a second messenger. So, the coincidence is detected because AMPA activation depolarizes the membrane, activation of NMDA with the depolarization to remove the magnesium activates the NMDA receptor, and the calcium comes in. So, not only do you have depolarization, but you have this calcium entry paired with it that initiates all the second messenger responses inside that initiates a metabolic program that recognizes that coincidence. The fourth thing that is unique about the NMDA receptor is that there is a necessary co-binding in what is termed the glycine binding spot. Now, as it turns out, it’s not only glycine that binds this spot, even though it’s always called the glycine binding spot, but also D-serine, which is another amino acid that is made in a very specific way. So, most amino acids are L-amino acids. D is a different isomer. It’s the opposite way of forming the same amino acid, and D-serine is made very specifically in certain places with a certain enzyme to act in a regulatory fashion. Even though books and even this text— I had to look this up in additional papers outside of the textbook, so this textbook describes the glycine binding spot. Many papers just refer to the glycine binding spot, but as it turns out, what’s out there in the literature is that at synapses, it’s not glycine that binds to that spot, it’s D-serine. Outside of synapses, you still have receptors on neurons. They’re not all located at the synapse. Even though that’s the main connection of one neuron to another, there are still receptors located on other parts of the neuron that are responding to ambient levels of things that escape the synaptic cleft or that got pumped out in a less specific way, and those non-synaptic, extra-synaptic NMDA receptors are the ones that use glycine as the obligate co-binding effector. Now, as it turns out, this coincidence detection that the NMDA receptor allows is a very key part of forming memories, and it’s been studied very well in the hippocampus, a major center where long-term memories are stored, for the concept of long-term potentiation. And long-term potentiation means that you, maybe not permanently necessarily, but permanently, or semi-permanently, or at least long-term, you increase certain synapses to strengthen them, and having long-term alterations in which synapses are strengthened is part of how you store memories. In the case of the hippocampus where this has been very well studied, one of the major effects is that the calcium that comes in through the NMDA receptors triggers processes that install more AMPA receptors in the membrane. So, remember, AMPA receptors are just how—that’s the normal receptor for excitation. NDMA receptor communicates that that excitation was paired with something that is interpreted as wanting to have that neuron be able to get excited more easily in the future. And what that does, the mechanism by which that happens, is to install more AMPA receptors in the membrane so that regardless of whether the NMDA coincidence happens in the future, that cell will immediately get excited more easily because of the greater AMPA receptors responding to glutamate with a more powerful response. An even greater way of doing the same thing is for that intracellular calcium that came into the NMDA receptor to actually initiate processes that make more synapses. So, not only do you have more receptor density at the synapse, but you make extra synapses that are even more intensively strengthening the same type of connection. Nowm while there’s long-term potentiation, or LTP, that strengthens connections and sensitivity, on the flip side, there’s long-term depression, or LTD, that weakens connections and sensitivity. The molecular difference between these two processes is that long-term potentiation, or LTP, processes are initiated by fast spikes of intracellular calcium, whereas long-term depression, or LTD, processes are initiated by slow, long leaks of intracellular calcium coming in. And as it turns out, it’s primarily the synaptic NMDA receptors that use D-serine as a co-agonist, meaning the thing that also has to bind in addition to glutamate, and it’s primarily extra— it’s primarily those that are engaged in LTP, and it’s primarily the extra-synaptic NMDA receptors that use glycine as the co-agonist that are involved in LTD. And before you go thinking of these as two opposite processes, in a way they are, but actually forgetting is super important to your memory. Think about what it would be like if you had to remember everything that you ever encountered. Well, you might think it’s a superpower, but actually it might be an enormous curse because not only would you have all these irrelevant, unimportant pieces of information clouding your mind, but moreover at some point, you’re just going to run out of room to store extra memories. So, LTD is incredibly important, even in the hippocampus, for making room to store enough memories as well as only holding onto the ones that make sense to hold onto. The hippocampus as the center of long-term memory storage also feeds in, among many other inputs, into the dopamine-dependent system of motivation. And so it’s probably the case that it’s not just remembering. When we think about memories, we’re thinking about what’s called declarative memories, which are memories that we can describe, but our memories are also nondeclarative memories, which are memories of things that go into knowing how to do something, but also they’re subconscious, stored memories that feed into what we’re motivated to pay attention to or what we’re motivated to stop paying
attention to. So, this LTD process is probably important not just to make room for memories and to be efficient about which memories you store, but it probably also— I, as a non-neuroscientist, would guess that it is also important for breaking bad habits and for remodeling the way that you do things because even if those memories are subconscious, they will feed into your behavior, and so if you’re trying to change how your past influences your current behavior, you need to depend on being able to erase those memories. In addition, one thing that’s known about epilepsy is that we can think of epilepsy as the condition that gives rise to seizures and seizures as the event of the seizure. Epilepsy seems to involve LTP that solidifies the seizure-producing network. In other words, you have a seizure for the first time, you become an epileptic, who is someone prone to seizures, because of remodeling processes involving LTP that strengthened the connections that lead to seizures. So although there’s no cure for epilepsy, it seems plausible to say that the right amount of LTD in the right places might help get rid of those connections or prevent them from going too far. So to summarize, to make glutamate, we require glucose, and we require niacin, and vitamin B6, and ATP. To clear it from the synapse, we need sodium and the energy from ATP. To avoid inappropriate activation of NMDA receptors, we need magnesium. To allow the production of D-serine, which is needed for LTP to strengthen connections, we need—and I didn’t mention this before, but the enzyme serine racemase that makes D-serine requires vitamin B6, and it appears to require copper and manganese. And then glycine by contrast is needed for LTD to weaken connections to allow the efficient storage of memories, and perhaps to prevent or break connections that have been made that are maladaptive. So that’s glutatmate. Next on our list is to talk about GABA and glycine, the two primary inhibitory neurotransmitters of the central nervous system. GABA is used in about one-third of brain neurons, which is the majority of the inhibitory neurons, and is about half-ish of the inhibitory neurons within the spinal cord. Glycine is half the inhibitory neurons in the spinal cord and also has inhibitory activity in the brain stem and the cerebellum. So, overall GABA is more widely distributed than glycine is, but glycine is still very significant in certain specific areas, and probably through its actions in the brain stem would be how glycine can lower core body temperature. It’s been shown that 3 grams of glycine supplementation before sleep will lower the core body temperature and allow you to get to sleep faster and have a more restful sleep. Glycine also, as we were just talking about, helps NMDA receptors mediate LTD, or long-term depression, and glycine is also a buffer of excess methyl groups, making it relevant to other neurotransmitters that intersect with methylation, such as dopamine and melatonin. Overall, glycine seems more relevant to homeostatic functions and coordination of movement patterns, for example, lowering the core temperature to help sleep. Its role in the cerebellum is probably related to the coordination of movements, since the cerebellum is mainly well-studied to have a role in coordinating movements and in motor learning. And GABA is probably more relevant to our perception of our senses, to our conscious movements, and our cognitive functions. But glycine does affect higher-order cognitive functions because of its buffering of excess methyl groups that affect things like dopamine. So, how do they work? GABA and glycine both work by binding to a receptor that opens a chloride channel. Remember, chloride is the primary negative charge, and usually it’s on the outside of the membrane. If you open a chloride channel, and the chloride comes into the cell, then the outside gets less negative, the inside gets more negative. The original resting potential had the inside negative. If the inside gets more negative, that is a hyperpolarization of the membrane. Hyperpolarizing a membrane brings it further—it gets further away from its threshold potential, makes it harder to excite, and that ultimately does nothing to that neuron, but it makes it so that the excitatory input is less able to bring the membrane potential to the threshold needed to initiate an action potential, so we call it inhibition. Although GABA and glycine are primarily inhibitory neurotransmitters, they can be stimulatory if chloride is not distributed so that more of it is on the outside than the inside. And I haven’t seen this studied specifically with glycine, but presumably the principle is the same because both of these are acting through opening chloride channels. It’s been well studied in the case of GABA, where if chloride is mostly on the inside of the membrane, then the effect of opening a chloride channel with a GABA receptor is to let the chloride out of the cell. If you let the chloride out of the cell, then you are you are depolarizing the membrane by lessening the degree to which the inside is more negative than the outside. Now, this is well studied in the case of newborns, where for a couple of weeks, there is very low expression of the potassium-chloride cotransporter, and there is expression of a sodium-potassium chloride co-transporter that brings chloride into the cells. So, you basically have—you’re basically deliberately creating an environment in the newborn where chloride is kept at high concentration inside the cell so that GABA will act as an excitatory neurotransmitter. And in that context, it’s acting to excite the growth and maturation of the nervous system that is critical to the first one or two weeks of life. But can that happen at other times? Well, certainly in the case of injury, you can injure a nerve cell in a way that the potassium-chloride transporter is not expressed in the membrane properly. And in that case, even in an adult who does not have a system designed for GABA to be excitatory, GABA might be excitatory. And this might be one of the things that contributes to epilepsy. Now, I mentioned before that the ketogenic diet is highly effective for epilepsy as a dietary treatment compared to the other options for dietary treatments and even even compared to many medications, but it doesn’t work for everyone. And it may be the case that if the ketogenic diet is primarily working by decreasing glutamate and increasing GABA, that it primarily works when the problem is that there’s too much glutamate or there’s not enough GABA, and probably does not work that great when the problem is that GABA is excitatory. So there are definitely some cases of epilepsy where the problem isn’t that you don’t have enough GABA. It’s that GABA is excitatory. And why is GABA excitatory? Well, no one really knows. We know that it’s because there’s—the chloride is concentrating inside the cell rather than outside, but we don’t know why, and it could be neuronal injury, but it could also be overuse of the GABA. So you have just too many excitation-inhibition cycles where the GABA has been—so much demand has been placed on GABA to stimulate the receptor so much to try to counter the excitation that you just used the GABA receptor one too many times and brought chloride into the cell using it one too many times that just exceeded the rate at which chloride is brought back out of the cell, so you keep firing, keep firing, keep firing the GABA receptor, and all the sudden, GABA starts doing the opposite. So, if that’s the case, you know something that increases GABA levels probably isn’t going to work that well. And indeed, several people have commented on my social media and my blog asking, how come when I take GABA I get this really strange excitatory effect from it? Well, I don’t know why, but I can pretty much guess that for some reason, there’s too much chloride inside your cells rather than outside your cells. So, I could speculate that a failure of energy metabolism would also produce this, right? Because to move chloride to the outside of the cell requires the ATP energy that created the potassium gradient that was used to bring the chloride out of the cell. So, that brings us back to, could it be magnesium, could it be the seven B vitamins involved in energy metabolism, could it be iron, copper, sulfur, could it be the nutrients related to preventing anemia, could it be insulin, could it be thyroid? Energy failure could certainly cause a lot of things to go haywire in the brain. Now, it’s generally thought that GABA, like glutamate, doesn’t cross the blood-brain barrier very well, and most or all of the GABA that’s in your brain is made in your brain, but in this case, there’s pretty good reason to think otherwise. So, first of all—well, I shouldn’t say first of all— basically the entire reason to think otherwise is that GABA supplements have effects that would appear to require the GABA to enter the brain. So, in humans a 100-milligram dose of GABA has increased the ratio of alpha brainwaves to beta brainwaves, and that suggests that it would be—that change in brainwaves suggests a better amount of effortless attention, and less difficulty concentrating, and less anxiety. There’s also an experiment where they had people who were afraid of heights cross a very long bridge that was very high up in the air, and they tested their salivary IgA, which is a protective type of antibody, and their idea in testing this was that the stress response very quickly and powerfully lowers salivary IgA. So, this was an easy way to measure whether the stress response of the heights was negatively affecting their physiology, and they found that the GABA supplement prevented the drop in salivary IgA that otherwise occurred as a result of crossing this bridge on foot. And this suggested that the fear of heights in these people, being exposed to what they were afraid of, had a less negative effect on their immune physiology. Additionally, there was a trial of 800 milligrams of GABA, where they found that it decreased reaction time on a stop-change test, which tests the quickness of you selecting actions among many competing options, and which suggests that this would improve your ability to make quick decisions about what to do under pressure. And this is particularly interesting because you think, well, GABA is inhibitory, shouldn’t it slow you down? But actually in this case, GABA is making you make decisions better and faster probably because it’s—the thing that it’s inhibiting is the competing options, and I’ll talk about this a little bit more when I talk about shifting attention later in this podcast. So, it would appear that GABA in foods is relevant if GABA in supplements is so relevant, and regardless of whether it’s getting into the brain, and I think it probably is, it’s doing something that impacts the brain, clearly. So, when we think about GABA in foods, we’re primarily getting it from foods that have been subject to fermentation by yeasts or lactobacillus bacteria. So, the minimum dose used in the studies that I cited to impact brain waves and salivary IgA in people exposed to their greatest fear of heights was 100 milligrams, and so if we think of 100 grams of a food as a standard serving, we can get 100 milligrams from whole wheat sourdough bread, we can get it from wheat germ, we can get it from just over 100 grams of barley bran, we can get it from two servings of foxtail millet, we can get it from japanese-style lacto-fermented fish, we can get it from half a serving of mustard leaf, or half a serving of adzuki beans, we can get it from two servings of some potatoes, but other types of potatoes are lower. Milk and cheese products can be high in GABA if they’re fermented right, but it seems most of the ones that are high in GABA have used specific strains of probiotics, specifically to make them high in GABA, and we can get it from less than half a serving of chocolate. I don’t have data on them, but probably most lacto-fermented things and most alcoholically fermented things have GABA in them, and pretty much anything that’s been fermented as something that is marketed as a strain of probiotic designed to increase GABA will be high in GABA. For example, there’s GABA-rich rice out there. Now, one thing that occurred to me when I was putting this together is, I really wonder if some of the people who feel that they are glutamate-sensitive are actually GABA-sensitive and if they just have an excitatory response to the GABA because there’s better evidence that the GABA gets into the brain, but that’s probably not a good argument if you’ve found that a GABA supplement has the opposite effect. So, if that were true, then you would negatively react to a GABA supplement. Now, dietary and supplemental GABA is relevant, but still, you’re primarily making GABA inside your nervous system, and when you do so, you make it from glutamate. You make it with the enzyme glutamic acid decarboxylase, which is dependent on vitamin B6. So, we needed B6 to make our glutamate, but we needed B6 to make our GABA from our glutamate, and for that matter, you cannot make GABA without glutamate. When you release GABA into the synaptic cleft, you do so through mechanisms that are almost identical to how you release glutamate into the synaptic cleft. To clear it, you use GABA transporters that are coupled directly to the sodium-potassium ATPase, just like the glutamate transporter is, and requires sodium and chloride, in other words salt. That GABA can reenter the neuron that uses it, called a GABAergic neuron as opposed to a glutamatergic neuron that uses glutamate, or it can be taken up and broken down in a two-step process depending on vitamin B6 and niacin, which is vitamin B3, to enter the citric acid cycle as succinate. So, we need glutamate to make GABA, and we need vitamin B6 and niacin to make glutamate. We need vitamin B6 to turn glutamate into GABA, and we need vitamin B6 and niacin to get rid of the GABA, and then of course we need energy, salt, and potassium to regulate the concentrations of these things all across the membranes. Now let’s turn to glycine, the second of this pair of inhibitory neurotransmitters. Glycine is an amino acid that is synthesized mainly from serine using, once again, vitamin B6 and the unmethylated form of folate. Folate is a key participant in the methylation cycle, which takes single carbon atoms and in this case delivers them to vitamin B12 so that vitamin B12 can allow them to enter the methylation cycle. If you don’t have B12, you can wind up with folate stuck with the methyl group. If it gets stuck in the methylated form, it is not able to participate in the synthesis of glycine from serine. In addition, you only have so many uses of folate for methylation, and you cannot make glycine without a supply of unmethylated folate. So if your need for glycine exceeds the amount of unmethylated folate that you have in any given moment, then your glycine synthesis will drop below that which you need. This is something that I explained in great detail on a podcast that I did with a couple of colleagues at chrismasterjohnphd.com/glycine. Glycine is needed for many other roles throughout your body, including synthesizing glutathione, the master antioxidant of the cell, detoxification in your liver, the synthesis of heme to make hemoglobin to carry oxygen in your blood, as I mentioned before, the synthesis of creatine, to synthesize collagen, that makes beautiful skin, that makes strong bones, and as I mentioned before, as a methyl buffer, and to allow glutamate to act through NMDA receptors in order to engage in LTD, long-term depression. But overwhelmingly, out of all of these, collagen is the biggest demand. And what we know from studies is that we can only synthesize about 3 grams of glycine a day, and in terms of our total needs to support our collagen synthesis, that may be falling anywhere between 10 and 60 grams per day short of our need. If you look at glycine in the diet, a low-protein diet will give you about a gram and a half, a high-protein diet will give you about 9 grams, but in that high-protein diet, especially if that diet is based on animal proteins, you have another amino acid, methionine, that both suppresses the synthesis of glycine and increases its loss. So a high-protein diet, even though it might give you 9 grams of glycine, might actually be worsening your glycine status rather than giving you more. I’m not against eating a lot of protein, but this is why I believe that when you eat a lot of protein, you need to match your muscle meats with your collagen-rich tissues. And if you think of how our ancestors lived, they ate the whole animal. They ate the animal nose-to-tail. Half of the animal carcass is collagen-rich tissues like bone. They used the bones. So our natural diets always paired the collagen-rich tissues that provided glycine with the methionine-rich meats that increased our need for it. So, from a glycine perspective, your worst position is to eat a diet very rich in animal muscle meats that is very low in collagen-rich tissues. A plant-based diet is kind of okay because the plant protein doesn’t tax your need for glycine as much and actually provides similar amounts of glycine without taxing your need for it as much. But if you really want to get, if you really want to maximize your glycine status, I do think including collagen-rich tissues and targeted glycine or collagen supplementation can be very helpful. And in terms of human studies, as I mentioned before, 3 grams of glycine prior to sleep has been shown to help you fall asleep and help you be more rested when you get up by making your sleep more effective. Sixty grams of glycine has been used as an anti-psychotic in the case of schizophrenia. I have a client who did not find that collagen before bed helped her sleep, and 3 grams didn’t work for her, but 6 grams did. So, I do think sometimes there’s a role specifically for glycine supplements, and I think in the case of sleep, it’s because when you don’t have the other competing amino acids from the collagen, the glycine gets into the central nervous system more effectively. When you release glycine into the synaptic cleft, you use the glycine transporter 2 to clear it, and that is dependent on sodium chloride, otherwise known as salt. That is also requiring, again, the energy from ATP to create the gradients involved in distributing the salt across the membrane properly. Moving on to acetylcholine. Acetylcholine uses acetyl CoA, which is made largely from glucose in the brain but can be made from ketones during extended fasting or a high-fat, low-carbohydrate ketogenic diet using vitamins B1, B2, B3, and B5, and then it takes the acetyl group of the acetyl CoA and combines it with choline, which you took up into the cell using sodium, and it’s combined to make acetylcholine. Acetylcholine, when it enters a synaptic cleft, has to be cleared. Unlike most other neurotransmitters, where you’re clearing it primarily via uptake into the neuron or a glial cell, in this case you’re primarily using the enzyme acetylcholinesterase, which is in the synaptic cleft, to break it down into acetate and choline, and then you bring the choline back up, and you resynthesize the acetylcholine. This is the basis for drugs that are acetylcholinesterase inhibitors that can be used, for example, to treat Alzheimer’s, which involves lower acetylcholine levels. Acetylcholinesterase inhibitors are also used for senile dementia, ataxia, which is incomplete control of your body movements, myasthenia gravis, and Parkinson’s. And there are natural acetylcholinesterase inhibitors in herbs like gingko biloba and bacopa monnieri. I’ll link to a paper that has an analysis of acetylcholinesterase and many other herbal concoctions, but this might be why these herbs have reputations for improving brain health, mental performance, and memory. While the acetyl CoA is coming from energy metabolism from glucose or ketones using the B vitamins, the choline is mainly coming in from your diet, although you can synthesize it using the methylation process, and the choline in the diet is primarily coming in in eggs and liver. There’s a smaller amount in nuts, cruciferous vegetables, and meats. See chrismasterjohnphd.com/methylation for much more detail about choline in the diet. Acetylcholine is the neurotransmitter that contracts your muscles. It’s also needed for performance during sustained attention. In deep sleep it declines, but in REM sleep, rapid eye movement sleep, it increases, and it’s highest in wakefulness. Choline is also needed as a methyl donor, as I mentioned before, and it’s important for phosphatidylcholine in the cell membranes, which is especially important to allow the export of triglycerides from your liver and thereby prevents fatty liver disease, which afflicts an estimated 70 million Americans and is highly associated with obesity, heart disease, and both type 1 and type 2 diabetes. In addition to acetylcholinesterase inhibitors, pharmaceutical or herbal, the supplement alpha-glycerylphosphorylcholine, or alpha-GPC, has been used to boost acetylcholine levels and to reduce the cognitive degeneration found in Alzheimer’s at a dose of 1,200 milligrams per day, dosed as 400 milligrams 3 times per day. I think alpha-GPC makes sense as a choline supplement if you feel like your primary problems are muscular weakness, and/or keeping your attention sustained for long periods of time, and performing well at tasks that require sustained attention. Interestingly organophosphates are toxins that are acetylcholinesterase inhibitors. And what they do is they cause your muscles to be exposed to so much acetylcholine that even though acetylcholine causes muscular contraction, your muscle cells desensitize themselves to the acetylcholine and become resistant to it, and so it causes paralysis. These organophosphates are particularly toxic to insects, and they cause this problem in insects at much lower doses than they cause it to us in humans, and so they’re used as insecticides. If you eat organic, you will have less exposure to organophosphates, and this has been shown by putting people on diets of organic food and looking at the organophosphate excretion in their urine. Now, is that a good or a bad thing? I suspect from a whole-body health standpoint, you want to eat organic, and I eat mostly organic, but it’s hard to say that this is a bad thing from an acetylcholine perspective because gingko biloba and the drugs used to treat Alzheimer’s are also acetylcholinesterase inhibitors. Maybe more targeted acetylcholinesterase inhibition from these herbs or drugs is better than eating dirty food, perhaps. Next we have the biogenic amines. Biogenic amines include the catecholamines, which are dopamine, norepinephrine, and epinephrine, and they also include histamine and serotonin. All of the biogenic amines are derived from dietary protein. These biogenic amines and others may also be found in foods, especially protein-rich foods that have been subjected to fermentation or to other processes, like storage, aging, or long cooking, that would cause the breakdown of some of the amino acids. But let’s focus on how we make them in our own bodies first. So, starting with the catecholamines, we begin with the amino acid tyrosine found in the protein that we eat. The first step is to convert tyrosine to DOPA, and that requires copper and iron, and there’s some evidence from animals that it also requires zinc, sodium, chloride, and a cofactor known as tetrahydrobiopterin, or BH4. There are rare genetic defects in the ability to synthesize BH4. For the average person, I think the main issue relating to BH4 is that it’s hurt during oxidative stress. Oxidative stress you could think of as the wear and tear on your tissues that happens with aging, but it accelerates with metabolic problems or with exposure to toxins, including lifestyle toxins, like tobacco smoke and alcohol, and it’s what you’re trying to counteract when you take antioxidant supplements. The next step is to convert DOPA to dopamine, and that requires vitamin B6, which keeps popping its head up. Dopamine itself is an important biogenic amine neurotransmitter that we’ll talk about in more detail momentarily, but dopamine gets converted using copper and possibly iron and probably vitamin C to norepinephrine. Norepinephrine then uses methyl donors from the system of methylation that we talked about before, dependent on folate, vitamin B12, and choline to get to epinephrine. Norepinephrine also goes by the name noradrenaline; epinephrine also goes by the name adrenaline. We think of these as adrenal hormones, and they are, but they’re also made in the nervous system as neurotransmitters, and in the nervous system, norepinephrine is more dominant than epinephrine. So, dopamine. Dopamine is necessary for healthy movement. We have the example of Parkinson’s, which is a degeneration of dopamine-synthesizing neurons that leads to tremors, especially in the hands, gait disturbance, balance issues, slowness, and weakness, and dopamine is also very important in motivation and reward. Drugs of abuse tend to target dopamine. But dopamine also signals the value of work and the willingness to put forth sustained effort over time to achieve something. Some people have suggested that, in fact, dopamine is a universal signal of value, and that in Parkinson’s when dopamine neurons start degenerating, it’s specifically impacting the areas where dopamine is signaling the value of movement, and the reason that the movement becomes dysfunctional is because the energy needed to control the movement and to make the person move is not recognized by the brain as having value worth putting in that energy. Dopamine does not signal pleasure. There is an absolutely enormous misconception in the popular discussion of dopamine that conceives of dopamine as a pleasure chemical that is associated with liking things. It absolutely is not. It is a motivational chemical that is associated with putting in sustained effort to obtain something. And this is a little bit more tangible when you’re talking about putting in the effort to obtain a physical reward in space, but it’s also impacting many pathways that allow you to shift what mood you’re in, for example, in which case dopamine is signaling the value of investing the energy in changing your mental state. It is fundamentally signaling that something has value. Value worthy of investment. Once dopamine enters the synaptic cleft, it has to be removed, and it is primarily taken up in a sodium-dependent process using the dopamine transporter. Again, we see the importance of salt. And there are two enzymes that are especially important in degrading dopamine. One is catechol-O-methyltransferase, or COMT, that methylates dopamine using the methyl donors we’ve talked so much about so far, and the other is monoamine oxidase, which uses riboflavin, vitamin B2, and copper to degrade dopamine. In fact, these enzymes are distributed differently in a way that makes these nutritional effects impact your mental stability and flexibility, and I will talk about that more when we get to the basal ganglia. Noradrenaline, or norepinephrine, is especially important as a signal for the sympathetic nervous system. Adrenaline, or epinephrine, is less prominent, but it’s more specifically associated with controlling your breathing and heart rate. Norepinephrine is also released from the brainstem in a way that impacts your choice to explore versus exploit. You can have norepinephrine either being pumped out tonically, meaning slowly in a continuous rate, or you can have phasic bursts of norepinephrine. The phasic mode is associated with exploiting a particular strategy, and the tonic mode is associated with exploring for other strategies. And it is not clear to me nutritionally if there’s anything you can do to impact one or the other, but I’ll link to a paper in the show notes that suggests that this is primarily being regulated by other neurotransmitters, especially dopamine, and I do know what nutritionally impacts that. So, we’ll talk about that a little bit when we get to the basal ganglia. But it appears that if you believe that what you’re doing now has very high subjective value, again, value, right, that’s regulated by dopamine, then your brainstem will be secreting norepinephrine in a phasic mode that will facilitate you exploiting that strategy and staying on that thing, whereas if what you’re doing now has lower subjective value, especially compared to the potential of alternatives, then that will trigger the tonic norepinephrine mode from your brainstem, which will promote disengagement from your current task and exploration of alternatives. Dopamine seems to be more related to the value judgment, and norepinephrine seems more related to actually energizing that program of behavior to either exploit or explore, and so they’re all connected, but exactly how one influences the other I don’t think has been worked out yet. Next up, histamine. You may know histamine as the thing that gives you allergic reactions. You may have taken an antihistamine because something was itchy or you were sneezing too much. If in fact you took an antihistamine, you may have noticed, depending on which one it was, particularly if it was benadryl, you may have noticed that that antihistamine knocked you out. And the reason is that histamine in the brain is what stimulates wakefulness, arousal, and attention. In excess, it can cause anxiety and panic, which you could think of as being a little too awake and a little too aroused. Like the catecholamines, histamine is made from the protein you eat, but instead of being made from tyrosine, it’s made from histidine, a different amino acid. That’s with histidine decarboxylase, which uses, guess what B vitamin, vitamin B6. In the brain histamine is overwhelmingly cleared with histamine N-methyltransferase, or HNMT, which uses methylation to clear it. Histamine elsewhere is cleared by the enzyme diamine oxidase, or DAO. So, if you’ve been following my Chris Masterjohn Lite episodes on histamine, you’ve seen me talk about DAO a lot, which is very relevant to clearing histamine in the foods you eat in your gut. But in your brain, methylation is what is overwhelmingly clearing your histamine. Now, interestingly histamine increases blood-brain barrier permeability, so it’s almost certainly the case that circulating histamine gets into your brain because histamine will increase its own ability to cross the blood-brain barrier. Now, that doesn’t mean that allergy causes panic attack because there’s a lot more going on, right? Your sensitivity to your histamine peripherally, meaning outside the brain, could be a lot higher than your brain sensitivity. Just because histamine crosses the blood-brain barrier doesn’t mean that anywhere near as much as is in your blood gets into your brain. The histamine that gets into the brain could be very effectively cleared by methylation, but you may not be able to control the release of histamine once it’s in your blood very easily. But some antihistamines have been effectively used for anxiety disorders, and on top of that, there was a very interesting study at an allergy clinic where they were trying to see if restricting dietary histamine, which is found primarily in fermented, aged, and dried foods, they wanted to see if it would help clear up skin problems. And although the diet, the histamine-free diet was not very effective at clearing up the skin problems, there were three people in the group who had panic attacks, and their panic attacks stopped when they went on the histamine-free diet. Now, I’m not an advocate of the histamine-free diet for panic attacks, but that just goes to show you that the histamine in your food and the histamine being released in your blood would appear to be able to influence histamine levels in the brain at a level that would control the state of arousal and make the difference between being just awake and attentive versus having anxiety and panic. Next up, serotonin. Serotonin is also known as 5-hydroxytryptamine, or 5HT. Serotonin, like histamine, is also involved in wakefulness, but it’s also important to emotional states, and motor behaviors, and circadian rhythms. SSRIs, or serotonin reuptake inhibitors, like Prozac, are used to treat depression. So, it would appear that not enough serotonin in the synaptic cleft can contribute to depression. On the other hand, LSD causes hallucinations by binding to one of the serotonin receptors, and stress-induced serotonin overload is thought to play a role in developing schizophrenia. So, too much serotonin in the synaptic cleft can cause some even worse problems than depression. I am not a psychiatrist, but if I were depressed, I would not use as my first line of resort stimulating a mode of action in the brain that causes the hallucinations of LSD and can cause schizophrenia, but please do not alter your medications based on my opinions without talking to your doctor. Serotonin, as one of the biogenic amines, is made from dietary protein, like histamine and the catecholamines, but in this case, rather than using tyrosine as with the catecholamines or histidine as with histamine, it uses the amino acid tryptophan. Interestingly, enough serotonin is also thought to mediate aversive learning to punishments, and it has been shown that restricting tryptophan in the diet will make humans less likely to change their behavior in response to being punished. In order to turn tryptophan into serotonin, you first turn it into 5-hydroxytryptophan, and you do that with an enzyme that requires BH4, which I mentioned before is in particular, takes a hit under oxidative stress.There are supplements on the market of 5-HTP that bypass that first step, the logic being that maybe you’re not very good at that step, which might be the case if you’re suffering from oxidative stress. Then the next enzyme converts the 5-HTP into serotonin using vitamin B6. Once serotonin enters the synaptic cleft, it has to be cleared, and it’s cleared using a sodium-dependent transporter and the enzyme monoamine oxidase, which is dependent on copper. Next up, we have ATP and the purines. Purines are the components of food that are associated with gout. If you look up a gout diet, you’ll see all the foods high in purines, and that’s because excess purines can generate uric acid, but you use purines, and you can synthesize your own purines. You use them to make the building blocks of things like ATP. ATP you may know as the primary energy currency of the cell, but ATP is also the primary excitatory neurotransmitter in the motor neurons of the spinal cord, which are the nerves that directly excite muscles using acetylcholine. ATP is also used in the sensory input into the spinal cord. So, you experience a sense, that sensation goes up the nerve to the spinal cord, it’s got to get into the brain, that signal is carried in some cases by ATP. Also, ATP is used as a neurotransmitter in the hippocampus, which is involved in consolidating long-term memories, like we talked about before. What do we need for ATP? Well, we need magnesium because everything ATP does, it does as ATP-magnesium, and we need all the vitamins and minerals that we talked about before involved in energy metabolism to be able to support ATP production. Outside the cell, ATP is degraded to adenosine, and that means that adenosine, unlike ATP, is not a classic neurotransmitter because it’s not released by a vesicle in a calcium-dependent fashion. But it still binds to receptors and has neurotransmitter-like activities outside the cell. Adenosine receptors are the things inhibited by caffeine and theophylline to antagonize its sleep-promoting effects. Oddly, the book doesn’t really discuss adenosine in sleep that much, but adenosine is one of the main signals of sleep pressure. So, as you’re awake, you get more and more adenosine accumulating outside the cells within your brain, and that makes you more and more tired. That basically increases linear through the day. Now, you might say, well, why don’t I get linearly more tired throughout the day? You know, I wake up at 8, I am not two hours tired at 10, and then twice as tired at 12, and then twice as tired at 4 o’clock. Rather, what’s happening is that you have increasing waking signals during the day that are counteracting the adenosine. And then the waking signal dips a little bit in the afternoon, and so you if you feel like taking a siesta, it’s because that adenosine is going higher and higher, but your waking signals dipped a little bit before they caught back up. Eventually your waking signals start to go down, adenosine is very high, and that puts the pressure on you to sleep. Well, caffeine comes in and says, “Oh, you feel tired? I don’t think so.” And that caffeine blocks the adenosine receptor and prevents it from carrying out its effects on sleep pressure, so if you do feel sleepy at 8 a.m., a little coffee might help. Finally we have the peptide neurotransmitters. There are many peptide neurotransmitters. Remember, these are the 3 to 36 amino acid long chains that are too small to be called a protein. Many of these are involved in the perception of pain, such as substance P, and beta-endorphin, and the opioids. All of the hypothalamic releasing hormones are examples of peptide neurotransmitters. So, technically although we call these hormones, they’re not endocrine hormones, which are hormones that leave one organ and travel through the blood to reach another. The hypothalamus is part of the brain, and it is directly structurally connected to the pituitary, which is the master endocrine organ. So, basically the hypothalamus-pituitary system is the interface between the brain, the nervous system, and the endocrine system. And if you’ve studied endocrinology at all, you’ve heard of things like the hypothalamic-pituitary-adrenal axis, or the hypothalamic-pituitary-thyroid axis, or the hypothalamic-pituitary-gonadal axis, and that’s because the hypothalamus directly injects these peptide neurotransmitters that we call releasing hormones directly into the pituitary, and the pituitary interprets that to release a hormone into the circulation that will then travel to the target endocrine organ and control the production of that hormone. So, for example, the hypothalamus injects TRH, or thyrotropin-releasing hormone, into the pituitary, that tells the pituitary to make TSH, or thyroid-stimulating hormone, that goes to the thyroid and has the thyroid make thyroid hormone. Or the hypothalamus injects CRH, corticotropin-releasing hormone, into the pituitary, the pituitary makes ACTH, adrenocorticotropic hormone, that goes to the adrenal glands to make adrenal hormones. Or the hypothalamus injects GnRH, gonadotropin-releasing hormone into the pituitary, the pituitary makes luteinizing hormone, LH, or follicle-stimulating hormone, FSH, that then act on the gonads, either the testes or the ovaries, to make sex hormones. Every single one of these hypothalamic releasing hormones is a peptide neurotransmitter. Another example is melanocyte-stimulating hormone, or MSH, which stimulates the production of melanin to pigment the hair, skin, and eyes. It also suppresses appetite and stimulates sexual arousal. Another peptide hormone is oxytocin. Oxytocin is the so-called love hormone. It’s involved in pair bonding and response to physical intimacy. Oxytocin is produced when a mother nurses her infant, oxytocin is released when you pet your dog, oxytocin is released when you hug someone for 20 seconds more than for 3 seconds, oxytocin is released during sex, more oxytocin is released if you orgasm, even more oxytocin is released if you love the person that you’re having sex with, and this stimulates attachment and all the other aspects of forming a bond between two people or between you and your dog. Another peptide neurotransmitter is vasopressin, also known as an antidiuretic hormone, or ADH. This is what stops you from peeing too much, and it is also what concentrates your urine to get rid of extra salt. So, when you want to pee less volume overall, you make more ADH, but also if you have salt that you have to get rid of, ADH reduces your urinary volume so that you can get a greater amount of salt in a lesser amount of urine and remove more salt from your body than you remove water. Nutritionally, these neuropeptides are very, very interesting. About half of all of the neuropeptides have an alpha-amide peptidylglycine residue at the end of their string of amino acids that is needed for their biological activity. How do you form that? Well, you need glycine, which we’ve talked about. You need zinc structurally for one of the enzymes, and as cofactors for the enzymes, you need copper and vitamin C. Which ones are those? Substance P, involved in the perception of pain. MSH, involved in the pigmentation of your hair, skin, and eyes, involved in appetite suppression and sexual arousal. Oxytocin, involved in the pair bonding response to physical intimacy. And vasopressin, involved in suppressing you from peeing too much. Now, this is interesting because not only do you need enough of all these nutrients, but you can imagine that perhaps some people have something impairing their transport of vitamin C into the brain. Were that the case, they might need high levels of vitamin C supplementation in order to get the right amount of vitamin C into the brain. Now, I’m just speculating about this, but there are a lot of people that claim to benefit in so many different ways from relatively high doses of vitamin C compared to what you get in the diet, then it makes you wonder. So, you might say, what would you expect if someone were deficient in copper or vitamin C. And maybe zinc here. I’m not sure. Maybe glycine. But let’s say something, one of these nutrients, glycine, zinc, copper, vitamin C is deficient in a way that’s specifically impacting this system. What would you expect if the alpha-amide peptidylglycine residue was missing from all the neuropeptides it’s known to be important for? Well, it could mess up your perception of pain. It could by affecting MSH reduce the pigmentation of your hair, skin, and eyes. Maybe that’s involved in the greying of hair, for example. It could make you eat too much and get a little bit fatter than you’d want to be. iI could make your libido go down. It could compromise your pair bonding response to the expression of physical intimacy, and it could make you pee too much. This sounds like a syndrome of things that a lot of people have just from getting older. In the last category of neurotransmitters, they termed them the unconventional neurotransmitters. These are something that are released using a calcium-regulated signal unlike adenosine, which is made outside of the cell, and they do participate in interneuronal signaling, signaling between one neuron and another, but they are not contained in vesicles, and they are not released by the mechanism of the vesicle fusing with the membrane. Among these, the ones that I think are most interesting to cover from a nutritional perspective are the endocannabinoids. These are named because they target the same receptor of THC found in marijuana smoke. I wrote an article years ago called “The Pursuit of Happiness” that I will link to in the show notes that discusses this, but the endocannabinoids are made from arachidonic acid, which is a fatty acid that is found mainly in liver and egg yolks. And you can make arachidonic acid from the linoleic acid found in vegetable oils, but it requires a lot of different nutrients, and it requires enzymes that are in limited supply, and there are a lot of health problems and genetics that can reduce its synthesis, so the easiest way to increase your arachidonic acid levels in your tissues is to consume arachidonic acid from liver and egg yolks. And these endocannabinoids have the effect of increasing dopamine to signal greater value and decreasing cortisol to signal lower stress. In animal experiments the higher the expression of these endocannabinoids, the lower the fear and the greater the exploration. So, in one model they have animals that are in kind of a home base that you could picture as being their comfort zone, and then they can go out of this little home base to explore, but they’re on a narrow, they’re kind of like on a narrow maze that is very elevated in the air, so it’s kind of scary to go out from the home base. But the more endocannabinoids they have, the further they’ll go out in search of food. When their endocannabinoid levels are
lower, they stick closer to their home base, even if there’s rewarding food outside of it because they’re too afraid to venture far out from their comfort zone. Now, there is recent evidence that there are endocannabinoids made from the omega-3 fatty acids EPA and DHA that are especially rich in fish. Arachidonic acid is the classical one, is an omega-6 fatty acid. You can also get DHA from algae, certain algae, and there are vegan capsules known as algae oil that contain DHA. And the science on the omega-3 endocannabinoids is much more recent, and so it’s hard to say what the importance is of balancing the different types, but probably it’s important to also have enough omega-3 fatty acids, and so don’t just eat your liver and egg yolks, but diversify your diet enough to include seafoods including fish, and if you’re a vegan, make sure you’re getting your algal DHA. This episode is brought to you by Ample. Ample is incredible. It’s a meal in a bottle that takes a total of two minutes to prepare, consume, and clean up. Two minutes. I’m not kidding. Now, I know you’re thinking anything that quick just has to be made of synthetic ingredients that you’d have a hard time pronouncing and wouldn’t want to put into your body, but it’s not. Ample is made entirely from natural ingredients and designed to provide an optimal balance between protein, fat, and carbs as well as all the vitamins and minerals that you’d need in a single meal. There’s no question that it’s always best to sit down and take your time eating a home-cooked meal from fresh ingredients, but let’s face it. Oftentimes we just don’t have time for that. If you live a busy life like I do, and your goal is to get things done, you need quality fuel that you can get into your system quickly. Here’s a great example where Ample is perfect for me. When I shoot videos, it takes hours to set up and break down all of my equipment. So I try to get as many videos shot in a day as possible. This prevents wasting a lot of time on setup and helps me conserve big blocks of time outside of shooting videos to get into a flow state where I can research something to my heart’s content and spend all the time I need thinking about it creatively and analytically, but if I spend hours dealing with recording equipment plus hours spent preparing food, eating it, and cleaning up, there’s like no time left over to actually shoot any videos. So on recording days, I use Ample to maximize efficiency and focus on getting things done. Ample comes in three versions: original, keto, and vegan. And each version comes in two portion sizes, 400 calorie and 600 calorie. The 600-calorie original version gives me 37 grams of protein from a mix of grass-fed whey and collagen, which promotes satiety and flips my brain on. Its fat comes from coconut oil and macadamia nut oil. I like these oils because they’re low in polyunsaturated fatty acids, or PUFAs, oils that promote aging and are usually loaded into the processed foods that most people eat when they need something on the go. The coconut oil provides some medium- chain fats to keep my energy levels up, too. The carbs, the vitamins, and the minerals all come exclusively from food sources like sweet potatoes, bananas, cocoa powder, wheat and barley grass, and chlorella. It’s full of natural prebiotic fibers and probiotics to promote a healthy microbiome and the gentle sweetness comes from a mix of honey, monk fruit, and stevia. I just mix it with water, drink it, rinse out the bottle, and boom, two minutes in and I’m fully fueled and ready to face the next phase of the day. I first came across Ample when I met its founder and CEO Connor Young at Paleo FX a few years ago. Connor inspired me with his vision for Ample, which I anticipate will be much more than a meal in a bottle in the near future. I’ve become an official advisor to Ample, and I’ll be helping Ample design scientific research that will lead both to an ever- improving Ample and I hope meaningful contributions to our understanding of how to use nutrition to help people be healthier and happier and perform better at the challenges that they care most about. As a listener to the Mastering Nutrition Podcast, I’ve also worked out a special deal for you. If you use the Discount Code CHRIS15, you’ll get 15% off your first order of Ample. To get your discount, go to amplemeal.com. That’s amplemeal.com, a m p l e m e a l.c o m, amplemeal.com, and use the code CHRIS15 at checkout. This episode is brought to you by Ancestral Supplements. Traditional peoples, Native Americans, and early ancestral healers believed that eating the organs from a healthy animal would strengthen and support the health of the corresponding organ of the individual. For example, the traditional way of treating a person with a weak heart was to feed the person the heart of a healthy animal. Modern science makes sense of this. Heart is uniquely rich in coenzyme Q10, which supports heart health. The importance of eating organs though is much broader than simply matching the organ you eat to the organ you want to nourish. For example, natives of the Arctic had very limited access to plant foods and got their vitamin C from adrenal glands. Vitamin C is important to far more parts of your body than simply your adrenals. In his epic work Nutrition and Physical Degeneration, Weston Price recorded a story of natives who cured blindness using eyeballs, which are very rich in vitamin A. But now that we understand vitamin A, we know that we can get even more vitamin A by eating liver, making liver good for your eyes. Our ancestors made liberal use of organ meats both to be economical and to utilize their healing and nourishing properties. Animals in the wild do the same. Weston Price had also recorded a story of how the zoos in his era were capturing lions, tigers, and leopards, oh my, only to watch them become infertile in captivity. Researchers then observed what the lions did when they killed zebras in the wild. What they did was they went straight for the organs and bone marrow, leaving the muscle meat behind for the birds. But even the birds took what they could of the organs and bone marrow. Price reported that once the zookeeper started feeding the animals organ meats, boom, their fertility returned. The problem I often encounter though is that many people just don’t like eating organ meats. Let’s face it, if you weren’t raised on them, it can be very hard to acquire a taste for them. That is where Ancestral comes in. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organ meats, living collagen, bone marrow, and more. All in the convenience of a gelatin capsule. For more information or to buy any of their products, go to ancestralsupplements.com. Ancestral Supplements. Putting back in what the modern world left out. If you’re liking this series and you didn’t see part one, go back one episode to see part one. If you want to see parts three and four for free, part three will come out next week, and part four the week after. But if you want all of these episodes right now and you want them ad-free with transcripts, then you can get your CMJ Master Pass for the all-access pass to early content to transcripts and other premium features and to the content free of ads at chrismasterjohnphd.com/pro. And you can use the code MASTERINGNUTRITION for a big discount. If you’re out and about in the interwebs, come and say hi. I’m on Facebook, Instagram, YouTube, and Twitter, @chrismasterjohn on every platform. I’ll see you out in the internet, or I’ll see you here in the next episode.