Benefits & Risks of Peptide Therapeutics for Physical & Mental Health

Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, we are discussing peptides. Peptides are a topic that's receiving a lot of attention these days, in part because of the excitement about the so-called GLP-1 analogs or agonists. GLP-1 stands for glucagon-like peptides. These are drugs used to treat type 2 diabetes, as well as drugs used to treat obesity. Today, we are not going to discuss the GLP-1 analogs. However, we are going to discuss some of the other peptides that are receiving a lot of attention these days, including peptides for tissue healing and repair, as well as peptides that impact longevity and vitality. Now, in principle, any discussion about peptides could be enormously vast, and that's because there are so many different kinds of peptides. And by the way, I will explain what a peptide is in just a few moments. But, for instance, insulin, which is involved in regulating our blood sugar or blood glucose levels, is a peptide. Oxytocin, which is sometimes called the love hormone, although I wouldn't say that's the best description of what oxytocin is, it's a neuropeptide/hormone that is involved in everything from pair bonding to socialization, but a bunch of other things as well. Those are just two examples of peptides that are familiar to most people, at least by name, and that exist within the tens of thousands, if not hundreds of thousands, of different peptides that exist within our brain and body. Today's discussion is going to focus on peptides that are increasingly being used for therapeutic purposes. And I want to point out something very important about this topic area. First of all, it is a topic area for which there is a lot of confusion. The mere naming of the peptides is confusing. Oftentimes, they're referred to simply by virtue of acronyms and numbers, like BPC-157 or MK-677, et cetera, et cetera. Such that if you're not really familiar with them, it can be a bit overwhelming and confusing. Today I'm going to provide a very simple organizational framework that will allow you to understand what these different therapeutic peptides are, why certain ones may be advantageous for certain purposes, of course also highlighting the potential risks and in some case outright dangers, and I'll tell you how they each work alone and in combination toward achieving specific physical and in some cases even mental health goals. I'd be remiss if I didn't say at the outset here that a lot of what's happening with applied therapeutic peptide biology falls into one of three categories. There are peptides that are being prescribed by physicians. So these are prescription peptides for specific purposes. These are FDA approved. There are other peptides that reside in kind of a gray market area. You can purchase them online, but the safety and efficacy of those peptides is a bit questionable, in some cases very questionable. And I'll give you some filters to determine which category certain peptides fall into. And then of course there's the black market peptides. It is possible to buy peptides online through any number of different sources. And of course I do not suggest people purchase black market peptides. It's very clear that a lot of them are contaminated with things that both in the short term, but especially in the long term, can be problematic. So if you're interested in understanding or using therapeutic peptides, today's episode is for you. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Mateena. Mateena makes loose leaf and ready to drink yerba mate. I often discuss yerba mate's benefits such as regulating blood sugar, its high antioxidant content, the ways that it can improve digestion, and possible neuroprotective effects. I also drink yerba mate because I love the taste. While there are a lot of different choices of yerba mate drinks out there, I love Mateina because, again, they have the no sugar variety, as well as the fact that both their loose leaf and their canned varieties are of the absolute best quality. So much so that I decided to become a partial owner in the company. Although I must say, even if they hadn't allowed me to do that, I would be drinking Mateina is the cleanest tasting and best yerba mate you can find. I love the taste of brewed loose leaf Mateina yerba mate, and I particularly love the taste of Mateina's new canned cold brew zero sugar yerba mate, which I personally helped them develop. If you'd like to try Mateina, go to drinkmateina.com/huberman. Right now, Mateina is offering a free 1-lb bag of loose leaf yerba mate tea and free shipping with the purchase of two cases of their cold brew yerba mate. Again, that's at drinkmateina.com/huberman to get the free bag of yerba mate loose leaf tea and free shipping. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods and different activities and your sleep patterns impact your health by giving you real-time feedback on your diet using a continuous glucose monitor. Now, blood glucose, sometimes referred to as blood sugar, has an immediate and long-term impact on your energy levels and your overall health. One of the best ways to maintain focus and energy throughout your day, as well as to keep your so-called metabolic health in best order, is to make sure that your blood glucose never spikes too much, nor does it get too low. With Levels, you can monitor how different foods and food combinations impact your blood glucose levels on a moment-to-moment basis. I've been using Levels for some time now, and it's really helped me understand which foods and food combinations, exercise schedules, and sleep schedules are optimal for my blood glucose levels and how that translates to energy levels and other metrics of health. If you're interested in learning more about levels and trying a continuous glucose monitor, you can go to levels.link/huberman. Levels has just launched a new CGM sensor that is smaller and has even better tracking than before. Right now, they're also offering two free months of membership. Again, that's levels.link l i n k /huberman to try the new sensor and two free months of membership. Today's episode is also brought to us by Juve. Juve makes medical grade red light therapy devices. Now, if there's one thing I've consistently emphasized on this podcast, it's the incredible role that light can have on our biology. And of course, I'm always telling people that they should get sunlight in their eyes as soon as possible after waking on as many days of their life as possible for sake of setting circadian rhythm, daytime mood, focus, and alertness, and improved sleep. Now, in addition to sunlight, red light and near-infrared light has been shown to have positive effects on improving numerous aspects of cellular and organ health, including faster muscle recovery, improved skin health and wound healing, even improvements in acne or that is removal of acne, reducing pain and inflammation, improving mitochondrial function, and even improving vision itself. What sets Juve apart and why it's my preferred red light therapy device is that it has clinically proven wavelengths, meaning it uses specific wavelengths of red light and near-infrared light in combination that trigger the optimal cellular adaptations. Personally, I use the Juve handheld light both at home and when I travel. It's only about the size of a sandwich. It's very convenient to use. I also have a Juve whole body panel and I use that about three or four times a week. If you would like to try Juve, you can go to joovv.com/huberman. Juve is offering an exclusive discount to all Huberman Lab listeners with up to $400 off select Juve products. Again, that's Juve j o o v v.com/huberman to get $400 off select Juve products. So, what is a peptide? A peptide is a small protein that's made up of little chains of amino acids. Now, the moment people hear protein, they usually think proteins that you eat or perhaps they think about four calories per gram of protein and that sort of thing. Keep in mind that we have lots of different kinds of proteins within our body that have nothing to do with the proteins that we eat. Now, it is true that many of the amino acids that comprise peptides, as well as other proteins in the body, come from the foods that we eat because the amino acids again are the building blocks of peptides and other proteins. The basic way that we define a peptide is that it tends to be a small protein, meaning chains of anywhere from two to 50 amino acids. That's really the strict definition of a peptide. However, oftentimes peptides that are a little bit bigger, so maybe 75 or 100 amino acids in length, will also be considered a peptide. Now, if you start combining different peptides together, you get what's called a polypeptides. And many of the proteins in the body are polypeptides. So, just to get a mental image of what a peptide is, a peptide basically looks like beads on a string where there are two to 100 beads and each of those beads represents a different amino acid and the arrangement of each amino acid relative to one another, that is, their order along that string determines what the peptide is and what the peptide does. The other thing that's important to understand about peptides is that some peptides are hormones, other peptides are merely called peptides proteins, others are neuromodulators, meaning they adjust the activity of neurons, and some peptides multitask and do many things. In fact, I think it's fair to say that most peptides have what are called pleiotropic effects, meaning they affect many different aspects of cells. And this is very important to understand because, unlike a lot of our discussion on this podcast about dopamine or about specific hormones like testosterone or estrogen. When we talk about peptides, especially therapeutic peptides, often times we're talking about a single peptide that does a bunch of different things depending on the cell type, the time of day or night that that peptide is present, and even the different so-called downstream effects of the peptide. What do I mean by downstream effects? Well, when a peptide binds to a receptor on a cell surface, okay, and you can just think of that process as a little parking spot on the surface of a cell, and the peptide if it's available, will bind to that receptor, and then set in motion a kind of bucket brigade, a sort of conveyor belt of cellular processes. For instance, activating one pathway for cellular growth, and another pathway for cell migration, for the cell to actually move, and maybe another pathway to talk to another cell to stimulate, say, the growth of blood vessels. In other words, lots of different or pleiotropic effects. This is important because when we're talking about peptide therapeutics, rarely if ever are we talking about a very targeted and very specific effect of these peptides. And this is important both in terms of thinking about what effects you're going to get of taking a given peptide if you decide to do that, as well as potential side effects, as well as things like how to adjust dosage and how long to take a peptide, whether or not to cycle the peptide, et cetera. So, I just gave you a very simple description of what a peptide is, and the fact that they have pleiotropic, meaning many different effects both within cells and across different cell types, and of course, across different organ systems. So, rarely if ever will you hear that a peptide does one thing. Most often a peptide does anywhere from four to maybe even a thousand different things. And again, we can go back to our basic examples of peptides like insulin, like oxytocin, and say, for instance, oxytocin, it's known to be involved in milk let-down during lactation. It's also known to be involved in pair bonding in both males and females, as well as pair bonding between parent and child, maybe even parent and pet. So, the point is that if you want a specific biological effect, maybe you want to repair a given injury, or you'd like to get more growth hormone in order, I don't know, to get leaner, or to recover from exercise more quickly, or to feel more vitality. Yes, there are peptides that can impact those pathways, but always, always, always, if you take peptides, especially therapeutic peptides, designed to promote activity within a given pathway for a specific purpose, you are going to activate other pathways as well. There's simply no way to remove the pleiotropic feature of peptide therapeutics. Nowadays, there's a lot of interest and indeed growing interest in peptide therapeutics. And there are really three different paths by which people obtain these peptides. The first is by prescription from a board-certified medical doctor. So, some peptides have been approved for one use, but they can be prescribed also for off-label use. And here we're talking about FDA-approved, clinically tested peptides. But in many cases, they've been clinically tested for one particular area of medicine. So, for instance, the peptide Sermorelin, which promotes the release of growth hormone, has been FDA-approved for the treatment of short stature, but it is often now prescribed for other things as well, where a physician and their patient agree that augmenting the growth hormone pathway would be useful. Now, regardless of the specific use in mind, it's absolutely clear that the safest and best situation, if one is going to use therapeutic peptides, is to use prescription therapeutic peptides, where the prescription comes from a board-certified physician. And the reason for that is severalfold. First of all, sometimes these peptides come from pharma companies, other times they are made by a compounding pharmacy. But in both situations, they are cleaned of what's called lipopolysaccharide or LPS. LPS is something that can accumulate in the manufacturing process of some of these peptides, and it's something that you really want to remove from the peptide before you ingest it or inject it. Most peptides are injected either subcutaneously or into the muscle, although some can be taken orally or even in a topical cream. We'll talk a little bit about different modes of delivery a little bit later. In any case, getting the LPS out and making sure that the peptide is pure is very important. The reason is that LPS causes an immune response. And while a tiny amount of LPS might not cause a massive immune response, the accumulation of many, many LPS exposures can start to become problematic. And the other sources of peptides, which are gray market and black market, often times do contain the same peptide that one would get from a prescription from a board certified physician, but very often they haven't cleaned out the lipopolysaccharide. They haven't removed the LPS, and that can start to create problems over time. And of course, in the case of black market sources especially, often times the peptides are not what they claim to be on the label or from a particular source. So, that's especially problematic. So, I want to be very clear about my stance on this. If you are going to explore peptide therapeutics, I highly, highly recommend, indeed I implore you to do so with a board certified physician and to acquire peptides through a reliable source where the LPS has been removed, which typically means from a pharma company or from a compounding pharmacy. Okay, so let's talk about specific peptides for specific purposes. Today, we're going to cover four general areas in which peptide therapeutics can be useful. The first is for rejuvenation and repair of basically any tissue, but in particular muscle and connective tissue, so sports type injuries, but also things like gut. So, for people that suffer from IBS, irritable bowel syndrome, or from colitis, or from other gut issues, there is a potential use for therapeutic peptides. Then we're going to discuss therapeutic peptides for metabolism and growth of frankly all tissues. As soon as people hear metabolism and growth, generally people think of fat loss and muscle growth, and indeed those fall under this category, but there are a bunch of other tissues for which you may want to improve metabolism and perhaps growth as well. So, we'll get into that. Then we'll discuss therapeutic peptides specifically for longevity, both staving off tumor growth as well as potentially, and I want to highlight potentially, increasing lifespan, although this is a very experimental area at present. And then we'll talk about therapeutic peptides for increasing vitality, both mood and libido in both men and women. Okay, so let's discuss peptides for rejuvenation and repair of tissues. Now, it's pretty common to injure a given tissue, you know, to uh you know, strain a tendon or tear a ligament or break a bone or I don't know, any number of different things. This is just kind of part of life if you uh play sports or if you exercise frequently, sooner or later people tend to get injured. And when one does, there's, you know, a lot of different things one can do. There's a lot of debate nowadays about whether or not you should emphasize cold or whether not you should emphasize heat. There seems to be a growing movement towards emphasizing the use of heat to increase blood flow to a given tissue as opposed to cold. We've covered some of this on other podcasts. We'll cover it more on future podcasts. But, you know, if you happen to injure yourself, typically what your physician will say is rest, maybe do some physical therapy. And indeed, those are excellent things to do, but one of course would ask, is there anything I can take in order to accelerate the healing of a given injury? And for that purpose, a lot of people over the years have explored the use of different peptides, in particular one that exists within the body naturally and that is involved in wound healing and repair. And that peptide is BPC, which stands for body protection compound 157. BPC 157 is a synthetic peptide. It's manufactured in a laboratory to resemble a peptide that exists naturally within our gut. Now, why would we have a naturally occurring peptide, a protein within our gut that's involved in wound healing and repair? Now, the answer to this isn't entirely clear. And as I always say, anytime you want to answer a question about kind of why something evolved to be a particular way, you have to remember that neither I nor anyone else who was involved in the design phase. It's just is what it is. So, we have to be careful about making up just-so stories about why something is doing what it's doing or how it got there. So, why would there be a peptide within the gut that's involved in tissue healing and repair? Well, in order to understand that, it's important to understand that the lining of your gut all along its length involves a bunch of different layers of cells that turn over at a pretty frequent rate. So, unlike your brain cells that for instance, after about age 25, you're not adding or deleting many brain cells, at least provided there's no injury or neurodegenerative disease, you're not removing a lot of those brain cells, but you're also not adding many brain cells. There are few areas of the brain like the olfactory bulb and the dentate gyrus of the hippocampus where there is some turnover, but for the most part, the neurons you have at about age 25 are the neurons that you're going to have for the rest of your life. Your gut is very different. Within the milieu of the gut, you have a lot of turnover of cells. And the turnover of cells in the gut is in many ways the same sort of turnover process that's involved in wound healing and repair. Like if you cut your skin, another tissue or organ, in this case, that involves a lot of turnover of cells because as you know, if you cut your skin, at some point, it will heal up. You know, first there'll be a scab, then that scab will give way as the tissue underneath it mends. And that mending of the tissue is the addition of new skin cells as well as other cell types. So, the fact that there is a peptide in our gut that can be involved in tissue turnover, and tissue turnover is equivalent to tissue repair, is not all that surprising. Now, it's important to understand that anytime we're discussing tissue rejuvenation, that is cellular turnover or tissue repair. So any kind of wound healing, a small wound or a big wound, it almost certainly is going to involve angiogenesis, which is development of new vascular supply or blood supply. Now of course, vascular supply arrives by capillaries, veins, and arteries. And typically when we're talking about angiogenesis in the context of tissue rejuvenation and repair, we're talking about the addition of new capillaries and or blood vessels. And that means the addition of new what are called endothelial cells, which are the cells that make up the walls of those blood vessels. So put simply, if you want to rejuvenate a tissue or you want to repair a tissue, you need additional blood supply. And one of the clear effects of BPC 157 is to both encourage cellular turnover as well as cellular migration, so new cells and cells moving into a given area, as well as new blood supply through the promotion of this process we call angiogenesis. So you can imagine for instance that maybe you injure your elbow and you do so in a way that impacts a bunch of different tissues. Maybe some of the nerve cells, the neurons there, are severed, okay, or crushed. So that might lead to some pain there, but it might also lead to some inability to move that joint or that limb as well as you could previously. Probably also some damage or some crushing to some ligament tissue and some tendon tissue, maybe even to some musculature. A bunch of different tissues are impacted. And one of the things that BPC 157 has been shown to do in animal studies, and I really want to emphasize animal studies because that's where the vast, vast, vast majority of data on BPC 157 come from, well, it's been shown to increase blood flow to a given area by virtue of increased angiogenesis. So basically to promote the development of new blood vessels to the entire injury site. And the way it does that is very interesting. BPC 157 somehow is able to recognize injured blood vessels and injured capillaries and then to promote the activity of a given enzyme called eNOS or endothelial nitric oxide synthase, which then causes more blood vasculature to form at the injury site and around the injury site. That in turn allows for the delivery not just of blood, but for the stuff that's contained within blood including growth factors that then promote the further rejuvenation of different cell types in the given area. So, the things that could potentially lead to repair of muscle, repair of ligament, repair of tendon, et cetera. And then BPC 157 is known to further encourage the growth of capillaries and veins within the injury area. So, it both calls in the development of new vasculature and it promotes the growth of that new vasculature. BPC 157 is also known from animal studies to encourage fibroblast migration and growth within a site of injury. Fibroblasts are a key cell type within an injury and they provide some of the really firm, strong substrate for bridging injuries and then allow different things like tendons and ligaments to restore themselves from say torn or partially torn to a complete tendon or ligament. Now, there's a very long and kind of interesting history of the use of gastric juices. Okay, I know the term might make a few people queasy, but gastric juices to promote tissue healing and repair. Now, there's a whole history of focusing on gastric juices or at least the stomach environment for keeping given tissues alive so that they can be repaired later. I know this sounds a bit gruesome, but one can find in the historical medical literature instances of people say severing off a finger or even a hand or things of that sort and then it being placed by a surgeon, of course, or in some cases these were battlefield situations into the gut as a way to preserve that finger or hand and keep it alive essentially and then to graft it back on or to make an attempt to graft it back on so that the person could then use those fingers or that hand again. And while not always successful, it was clear, or at least the idea started to form that tissues that were placed inside the milieu of the gut stood a better chance of being grafted back on. Now, you could think of a number of different factors that could impact the improved grafting of tissues placed in the gut until the graft could take place. You know, it could be the heat of the environment. It could be the fact that the hand or finger is not exposed to things out in the world, so less bacteria, etc. Nonetheless, physicians were intrigued by the idea that maybe something within the gut itself, and in particular within gastric juices, were beneficial for preserving and maybe even rejuvenating tissues. And one particular peptide compound turned out to be BPC, body protection compound, which again is synthesized as BPC 157. So, there's a real logic here, but what we haven't really addressed is if one has an injury, let's say to the hand or um to the arm, or to the leg, or to the ankle, or to the Achilles tendon, how is it that body protection compound that normally would exist within the gut actually access that injured tissue? Now, this still remains somewhat of a mystery. It is clear that BPC 157 can exit the gut, but how it gets trafficked to particular sites within the body that are injured still isn't clear. That said, within the community of people that use BPC 157 for therapeutic reasons for tissue rejuvenation and repair, there's sort of been an ongoing debate as to whether or not you can take it systemically, that is to inject it or even take it orally, and that it will find the site of injury, right? It'll go direct itself to the site of injury, or whether or not it's more beneficial to inject it directly to the site of injury. And here, there's really no formal science. I want to be really clear. When we talk about BPC 157, we can look to a pretty large literature of peer-reviewed studies dating back to about 1993 is when the first kind of rigorous study of BPC 157 really began. And there are a lot of studies in rats, in mice, and a few other species as well. To my knowledge, there is only one study on humans, and it's not a clinical trial, and frankly, it's not the best performed study, and that's putting it mildly. It's more um kind of self-report of people recovering from a given injury, whether or not they took BPC 157 or they didn't. So, when we talk about BPC 157, we're talking about a pretty unusual circumstance, whereby many, many people are now taking it. Very likely hundreds of thousands, perhaps even now into the millions, but we actually have essentially no human data as to how BPC 157 works in humans, and why it does seem, because this seems to be the quote-unquote anecdote to accelerate healing of a variety of different injuries. Okay, so it's an unusual circumstance, and it's kind of an unusual thing for us to talk about here on the podcast. Yes, we've talked about supplements, and yes, we've talked about different hormone therapies, and yes, we've talked about any number of different things, but it's pretty unusual to have so much animal literature. I even would go so far as to say quality studies of BPC 157 and its effects in animal models such as rats and mice, and such a dearth of formal rigorous exploration of BPC 157 in humans, and at the same time a gosh, let's just call it what it is, a really rich set of anecdote, meaning that many, many people, perhaps even most people who take BPC 157 by the way, the typical route of taking BPC 157 is either to inject it subcutaneously or into the muscle, and to do that, regardless of where the injury is, they'll do that in one particular site, so subcutaneously just a few inches off the belly button, or into um you know, into the shoulder or something of that sort if they're doing it intramuscularly, or in some cases people will direct it to the site of injury by injecting more local, like if you have an elbow injury, they'll put it into the muscle right above the elbow, or subcutaneously right above the elbow. And we're now in a situation where we don't know if we're dealing with pure placebo effect or we're we are dealing with real effects. And so, because of the lack of the human clinical studies, we don't know whether or not we're dealing with a situation of robust placebo effects. I did an episode all about placebo effects, and placebo effects are and can be oh so real. They really um can really trick you into thinking that a given compound is doing something when in fact it's not doing anything different than would an injection of saline, of salt water. But, in this case, there's just such an overwhelming amount of what I call anecdote. And there's so many people using BPC 157 now and are interested in starting to use BPC 157 that I'd be remiss if I didn't discuss it despite this gap in the human clinical literature. So, what do we know from the anecdote? The anecdote seem to indicate that the mode of delivery, that is whether or not systemic or local, doesn't seem to matter that much. Although some people, for whatever reason, will purport that local injections serve recovery of the tissue more readily than systemic injections. Now, there are a couple things to understand about BPC 157 besides the fact that in animal studies it's been shown to increase fibroblast migration to a site of injury, as well as endothelial cell and vascular growth to a site of injury. And the first thing is that injury seems to be important. There does seem to be something that the injury signals to BPC 157 to create new vasculature and fibroblast growth there at the site of injury. There's no evidence from these animal studies, at least to my knowledge, that BPC 157 systemically increases vascular growth, although one could imagine that it might, right? And for that reason, I'll talk about some cautionary notes about BPC 157 as it relates to tumor growth and cancers and diseases, in particular of the eye, that involve overgrowth of vasculature. But before I do that, I want to talk a little bit about the safety of BPC 157. One of the reasons why it's being used so extensively is that it does seem to have very high safety profiles at least with respect to the lethal dosing, right? In order to find out the lethal dose of something, as you can imagine, unfortunately, the way these studies are done is they give animals more and more, that is higher and higher doses of a given compound, find out at what point about 50% of the population of those animals starts to die, and then that's the so-called LD50, or at least that's one crude way of describing it. The LD50 of BPC 157 is incredibly high, okay? It is as high as 2 g, okay? 2 g, 2,000 mg, that is, per kilogram of body weight. Now, that does not mean, please hear me on this, that does not mean that anyone should be taking high dosages of BPC 157. The typical therapeutic doses that are prescribed are anywhere from 300 to 500 micrograms subcutaneously, maybe two or three times per week. And that is typically done for a course of about 8 weeks, and then people typically cycle off for anywhere from 8 to 10 weeks. Now, when I say typically, I mean typically, because there are individuals that take BPC 157 consistently. They just take it every day, and they'll just take it indefinitely without any breaks. I think that is a bad idea. And I want to also state that I am not suggesting anyone run out and take BPC 157. Today's episode is really about giving you information so that you can make the determination whether or not you even want to take BPC 157 or another peptide, and of course to really seriously consider the sourcing issue that we talked about earlier. Now, what would be a reason to avoid taking BPC 157? Well, the first relates to something that many people take BPC 157 for because they believe it's good for them, and in some cases, potentially could be, which is that in addition to increasing fibroblast migration and angiogenesis, blood vessel development, within a site of injury, BPC 157 is known to have a small, but nonetheless meaningful impact on upregulating growth hormone receptors. Now, this can be a good thing if you're trying to upregulate growth hormone receptors at a given injury site so that growth hormone, which comes from the pituitary and that we'll talk a bit about more later, then can have a heightened level of action at that tissue and growth hormone is involved in tissue turnover and repair. Now, this is evident from childhood where kids heal from wounds much faster than adults heal from wounds. There's other reasons why kids heal from wounds more quickly than adults that relate to things like stuff we secrete from the thymus, etc. We'll talk about that as well. But this idea of increasing growth hormone receptors at the site of injury or around the site of injury by injecting BPC 157 locally to the injury or even taking it systemically is one thing that many people think of as advantageous and that's why they want to take BPC 157. However, for some people, perhaps people who have a tumor in a given area, an increase in growth hormone receptors in and around the tumor could potentially increase the growth of the tumor. And that's one of the major issues with BPC 157 that's not often discussed, which is that if you have a tumor and tumors thrive on increased blood flow because they like to consume growth factors and increased blood flow means increased growth factors and other things that can not just sustain but actually grow the tumor, well then by taking BPC 157 you may be either maintaining or accelerating the growth of a tumor that would otherwise be removed or stay small. In other words, BPC 157 is a potential tumor growth risk. So, if you have knowledge of a given cancer or you're concerned about tumors at all, I would encourage you to be very cautious about the use of BPC 157. In fact, one way that BPC 157 creates this increase in angiogenesis, this increase in vasculature, is through upregulation of something called VEGF, VEGF, which is vascular endothelial growth factor. Now, there is a common treatment for cancers, which is Avastin. Avastin is a VEGF inhibitor. It's a drug that's designed to fight tumors, to reduce tumor size, and does so by inhibiting VEGF. Whereas BPC 157 is doing the exact opposite. It is increasing levels of VEGF to increase angiogenesis. So, by logical extension, if you're concerned about tumors or cancer of any kind, BPC 157 is probably not something that you want to explore. So, if BPC 157 carries these risks, why are so many people interested in taking it or taking it? I think in large part that's due to the fact that um the anecdote about BPC 157 is just so strong. People report all sorts of things, like, you know, they recovered from their shoulder injury much faster. There are these kind of outrageous claims about people recovering from complete tissue transections. And um indeed, there are the animal data are pretty impressive. I went into the data that looked at sciatic nerve regrowth after injury, Achilles tendon regrowth after injury. And some of these studies in rats involved a complete transection, not just a partial tear, but a complete cut of a given ligament or tendon or nerve pathway. And indeed, the data are pretty impressive that when BPC 157 is applied systemically, right? So, given, you know, at the level of the gut, somehow it's able to travel to the site of injury, recognize that something needs to be done there, in particular angiogenesis and fibroblast infiltration. And it does seem that on average that these tissues repair faster than they do if BPC 157 is not provided. But again, the tumor concerns and the lack of human data are a real concern that everyone should be made aware of. I do not think that BPC 157 is not without its quote unquote side effects. I do think that we are now in a state of widespread experimental use of BPC 157, even though it can be obtained clean without LPS from compounding pharmacies and by prescription. There are a lot of people taking BPC 157, and I just want to return to the point I made earlier, which is that, you know, BPC-157 is typically taken in these dosages of about 300 to 500 micrograms, you know, two to three times per week, maybe even 5 days per week. If you're going to go down this path of taking BPC-157, I would encourage you to take the minimal effective dose, to not simply do it every day, and certainly to not do it continuously, and of course to monitor your other health metrics for anything that could potentially resemble cancer or tumor growth, because obviously stimulating angiogenesis for wound repair sounds like a great thing, recovering and being able to do your workouts or play your sport or um move about more comfortably, of course, uh a wonderfully attractive thing to do, isn't that what we all want, but obviously not with the trade-off of growing a tumor or developing a cancer or accelerating a cancer. I'd like to take a brief moment and thank one of our sponsors, and that's AG1. AG1 is a vitamin, mineral, probiotic drink that also contains adaptogens. I started taking AG1 way back in 2012. The reason I started taking it, and the reason that I still take it every day, is that it ensures that I meet all of my quotas for vitamins and minerals, and it ensures that I get enough prebiotic and probiotic to support gut health. Now, gut health is something that over the last 10 years we realized is not just important for the health of our gut, but also for our immune system and for the production of neurotransmitters and neuromodulators, things like dopamine and serotonin. In other words, gut health is critical for proper brain functioning. Now, of course I strive to consume healthy whole foods for the majority of my nutritional intake every single day, but there are a number of things in AG1, including specific micronutrients, that are hard to get from whole foods or at least in sufficient quantities. So, AG1 allows me to get the vitamins and minerals that I need, probiotics, prebiotics, the adaptogens, and critical micronutrients. So, anytime somebody asks me, if they were to take just one supplement, what that supplement should be, I tell them AG1, because AG1 supports so many different systems within the body that are involved in mental health, physical health, and performance. To try AG1, go to drinkAG1.com/huberman and you'll get a year's supply of vitamin D3K2 and five free travel packs of AG1. Again, that's drinkAG1.com/huberman. Okay, so we're still talking about peptides for tissue rejuvenation and repair. And we spent quite a bit of time on BPC 157 because that's one getting a lot of attention nowadays. There's another one that's getting increasing attention that's worth mentioning, which is thymosin beta 4 and a related peptide, which is TB500, which is basically a truncated or a shortened version of the thymosin beta 4 peptide. Remember, the peptide are these strings of amino acids like beads on a string. And thymosin beta 4 is something that the body produces naturally from this thing called the thymus, which is present in children and then disappears as we get older. And it's well known, again, this is correlative, but it's well known that children recover more quickly from injuries. And indeed, the degree of tissue regrowth and the repair of wounds with minimal scarring is so much greater in young children and in children than it is in adults. And this is what gave rise to the idea that perhaps some of the peptides that are secreted from the thymus, such as thymosin beta 4, could be involved in tissue rejuvenation and repair. And that's what led to the laboratory synthesis of thymosin beta 4, the full-length peptide made in a lab, not by the thymus, and then adults take it, okay? Or TB500, which is this truncated, slightly shortened version of thymosin beta 4, which acts similarly to thymosin beta 4, but has a kind of different mode of action, lasts a little bit longer, etc. Now again, we're in a situation where there are vast amounts of animal data, studies on mice or rats, typically, that show that thymosin beta 4 can increase the rate and/or thoroughness of wound healing and repair. But again, there are more and more people now now thymosin beta 4 for the purposes of tissue rejuvenation and repair and report positive effects. Now, when we say positive effects, we have to stand back and say, well, um what's the control experiment? What you know, how would they know how quickly they would heal without the thymosin beta 4? And there's simply no way to address that question. You know, my whole purpose in doing this episode is to highlight how these different molecules ought to work, how they've been shown to work in animal models, and therefore how they might be working in humans. But again, in the absence of clinical trials, we still don't know if and how they are working in humans. Nonetheless, a lot of people are now starting to take especially TB-500. It's often taken in combination with BPC-157. And at the level of mechanism, the difference between BPC-157 and thymosin beta 4 is that thymosin beta 4 really promotes the growth and infiltration of all sorts of different cell types associated with tissue rejuvenation and especially wound healing and repair. It's been shown to promote stem cell proliferation. It's been shown to increase the growth of the so-called extracellular matrix, the stuff around the cells that keeps the area around the cells kind of rigid so that um the tissue or the organ has more stability, right? You can't just have a bunch of cells with um a bunch of empty space around them where they can move about. You want to have some rigidity to the whole thing. So, the idea is that thymosin beta 4 is promoting the aggregation of a bunch of things associated with tissue healing. I've noticed out there that a lot of people talk about TB-500, that is thymosin beta 4, in the context of being growth promoting. As far as I know, it isn't growth promoting. It doesn't impact the growth hormone pathway or other pathways associated with tissue growth. Rather, it's involved in tissue repair. So, what I just discussed are the two major players or the two most often used peptides nowadays for tissue rejuvenation and repair. We've got BPC-157, which you can just basically frame up in your mind as promoting angiogenesis and wound repair through a variety of mechanisms, but mainly the addition of new vasculature to the wound site. And then we've got thymosin beta 4, which is sometimes referred to as TB500, which is just a shorter synthesized version of thymosin beta 4, which is a molecule known to come from the thymus in children. Whether or not it's solely responsible, I doubt it's solely responsible, in fact, for the better tissue healing and repair seen in children as opposed to adults. We don't know, and yet it does seem, at least anecdotally, that people are taking TB500, again, either alone or in combination with BPC 157, and at least to their mind are reporting more thorough or more rapid tissue rejuvenation and repair. So, the next category of peptide effects that I'd like to talk about are the effects of certain peptides on metabolism and growth. And any discussion about metabolism and growth, by definition, has to include a discussion about growth hormone. So, basically, where we're headed is a discussion about peptides that can increase amounts of growth hormone that are released in our brain and body to have specific effects, in particular, increases in metabolism and increases in either muscle growth and, in some cases, repair of tissues as well, although mainly muscle growth and fat loss. For those of you that aren't familiar with growth hormone, growth hormone is a hormone that we naturally make. It's secreted from a gland called the pituitary gland. The pituitary sits near the roof of the mouth, and it extends out of the stalk of the brain such that it can release hormones into the general bloodstream. The pituitary is connected to the brain, however, so it can get input from a brain area called the hypothalamus, and within the hypothalamus, there are neurons that can send signals to the pituitary telling it to either release growth hormone or to suppress the release of growth hormone. Now, early in life, when we are infants, children, teenagers, and so on, we secrete tons of growth hormone, in particular, during the early hours of sleep each night. We also secrete growth hormone a little bit throughout the day, but it's really in sleep in which we have the greatest degree of growth hormone release. This is one reason why babies and kids and teenagers sleep so much is there's a lot of growth hormone release and we tend to grow, that is the tissues and limbs of our body tend to grow during sleep. Now, it's been well documented that after about age 30, which is typically when people experience their full stature, their full height, although sometimes there's a little bit of wiggle room around that age, typically after 30, the amount of growth hormone that's released each night and throughout the day is reduced by about 15% for every decade of life. As a consequence, all of the things that growth hormone does like encouraging higher metabolism, fat loss, the growth of muscle tissue, etc., is dramatically reduced as we go from 30 to 40 to 50 and on and on. It's also the case that naturally released growth hormone tends to have positive effects on our mood and overall feelings of well-being. So, it's also tied to our feelings of vitality or having feelings of energy to do things. And that's because growth hormone potently increases ATP production, which is involved in energy and metabolism in our cells and as a consequence our overall feelings of energy to just do things, mental or physical. Now, there's another hormone called IGF-1 or insulin growth factor 1, which is produced by the liver. Insulin growth factor 1 does many things similar to growth hormone and it actually is released in response to growth hormone. So, basically the way this works is that there's a signal that comes from the hypothalamus called growth hormone releasing hormone and then that signal stimulates the anterior pituitary to release growth hormone. Growth hormone then is circulated throughout the blood. It also can access the brain itself and it does different things in different tissues, but again, increases ATP production for energy. It is going to cause tissue repair in some cases. It's also going to encourage growth of tissues, not just muscles, but other tissues. That's why it's involved in helping us achieve our full height, our full stature. When growth hormone reaches the liver, it stimulates the release of IGF-1, which in turn does a number of things that are both synergistic and different. That is, it works both similarly to growth hormone and does some things in parallel that are a little bit different as well. In particular, things related to regulation of blood sugar metabolism, etc. All things associated with kind of youthfulness, vitality, and energy. So, it's impossible for me to say that growth hormone and IGF-1 do just one thing each. They do lots of different things in lots of different tissues. But, hopefully from the description I just gave, you could see why some people might be interested in augmenting or increasing levels of growth hormone. Now, growth hormone has been sequenced and synthesized, so you can buy a synthetic version of growth hormone. And indeed, some people will take prescription growth hormone. They'll take this by typically it's an injection that's given subcutaneously at night, and they achieve growth of tissues including muscle, etc. Keep in mind that growth hormone is indiscriminate with respect to which tissues it grows. So, if you happen to have an existing tumor on a given body part or within a given body part, it will encourage growth of that tumor as well. That's one of the reasons some people are cautious about taking growth hormone. Another reason why many people are cautious about taking growth hormone is that it is subject to what's called negative feedback. If your blood levels of growth hormone are too high by virtue of injecting growth hormone, well then the pituitary can register that and the brain can register that, and then there's a negative feedback that shuts down growth hormone. As a consequence, people have developed peptide therapeutics that stimulate the release of growth hormone and thereby the release of IGF-1, but not by directly stimulating the growth hormone pathway. Typically, what these peptides are are these are peptides that mimic the sorts of things that are typically released from the hypothalamus onto the pituitary, and in that way stimulate the release of growth hormone and downstream IGF-1. So, what these things are typically called are secretagogues. These are peptide molecules that have been synthesized in a laboratory that stimulate the release of growth hormone and thereby stimulate the production of IGF-1. Now, there are two general categories of peptides for stimulating the release of growth hormone. The first category often times are referred to as the GHRH peptides for growth hormone releasing hormone peptides. Now, that name has certain problems that we'll get to in a moment, but let's just leave it there for the time being. The second category are what's called the growth hormone releasing peptides, right? Before we said growth hormone releasing hormones, that's the first category. Second ones are the growth hormone releasing peptides. You can already tell why this is getting confusing. Here's what I'm going to do. Rather than use that nomenclature, which is the typical nomenclature that's used, and I must say for which there's a lot of errors when I look out there on various YouTube videos and I look within even some of the reviews that have been written, people get things confused as to whether or not a given peptide that one would use as a therapeutic falls into one or the other category, and you'll see in a minute it's a really important distinction. Instead, what I'm going to call these are category one peptides and category two peptides. Okay? In general, category one peptides are going to be the ones that have been most thoroughly tested in humans, in some cases, in fact, in several cases, are FDA approved for certain conditions, and yes, are prescribed for other off-label effects. Again, this would be under what I'm calling type one growth hormone secreting peptides is sermorelin. Sermorelin is a synthetic compound designed to mimic naturally occurring growth hormone releasing hormone that is FDA approved for the treatment of short stature. So, you can get this by prescription, sometimes it comes from a compounding pharmacy, other times it comes directly from pharma for the name brand. In any case, sermorelin has been shown to mimic what is normally released from the hypothalamus and stimulates the pituitary to release growth hormone, and it does indeed cause increases in circulating growth hormone and increases in IGF-1. By the way, the typical dosages of sermorelin that are um taken are anywhere from 200 to 400 micrograms. Typically, that's done at night before sleep for the reasons that we talked about before. And typically, people will take it anywhere from three times per week or five times per week. There are some disadvantages to taking it continuously 7 days per week for long periods of time. There's some desensitization that can occur. Not much, but some can occur. So, taken in that way, sermorelin has been shown to increase circulating levels of growth hormone and IGF-1. And the reason why a lot of people seek to take sermorelin is because they like the effects it produces. They like the vitality, they like the muscle growth, they like the fat loss. Um it also can increase the amount of deep sleep that you get. I'll just be completely forthcoming. I've taken sermorelin on and off for the last couple of years. I typically will take it anywhere from one to two nights per week. And I stopped taking it almost completely. I'll still take it every once in a great while. But the reason I stopped taking it is that I noticed that it made the sleep in the early part of my night very, very deep, very robust. But then I would wake up wide awake, or I would sleep till morning, and then at least according to my eight sleep sleep tracker or my Whoop sleep tracker, I wasn't getting nearly as much rapid eye movement sleep as I normally would. So, at least in my case, and again, this is anecdota, it seemed to sort of replace rapid eye movement sleep with more deep sleep. And rapid eye movement sleep is critical for all sorts of things that deep sleep can't achieve and vice versa. You really want both. So, this is one reason why I've basically stopped taking sermorelin. I'll occasionally take it every once in a while. But in general, I just, you know, stopped taking it because whatever the positive effects might have been if I had taken it more consistently, the effects in depleting rapid eye movement sleep were just something I didn't want and don't want. And by the way, that effect on increasing deep sleep, that non-REM sleep, is something that's pretty well documented. The other what I'm calling type one growth hormone promoting peptide is tesamorelin. This goes by the brand name Egrifta and it's an FDA approved drug for the reduction of visceral adiposity in HIV patients. So, we have subcutaneous fat and we have visceral fat around our organs. Visceral fat can be really problematic and for some people who have HIV or and for people who don't have HIV, the deposits of visceral fat can be problematic for their health and tesamorelin, again also called Egrifta, has been shown to reduce visceral adiposity. It also seems to produce some of the other same effects that sermorelin produces. The differences between the two relate to small differences in the amino acid sequence for one peptide versus the other. Tesamorelin is a bit more long-lasting than sermorelin and therefore is taken typically about three times per week, not five times per week. Now, the third most commonly used peptide in this category of what I'm calling type one growth hormone secreting peptides is CJC-1295. Gosh, I wish there was a an easier name. CJC-1295 is basically a variant of a different growth hormone secreting peptide that was synthesized previously to which they add what's called a DAC, a drug affinity complex. It's a It's a sequence that makes it very long-lasting. So, CJC-1295 typically is only taken twice per week or even once per week because its effects on increasing growth hormone and IGF-1 last several days, which may sound great to you, especially if you're somebody that doesn't like um taking injections because these things in general have to be uh delivered by injection. But, keep in mind that CJC-1295 has entered clinical trials. There was a death within one of the clinical trials that was related to cardiovascular dysfunction. It's known to cause some fluid retention and increased fluid volume, which may be have been related to that cardiovascular death. We don't know, okay? This is all kind of speculation. But, I would say if you are somebody considering using a growth hormone secreting peptide, the type one category is perhaps, and I'll give my explanation for why I believe this to be the case, perhaps the most advantageous category to explore. And as I mentioned before, you've got the options of sermorelin and tesamorelin, both of which are FDA approved and for which there's both animal and human data. CJC-1295, despite still being in clinical trials, does have this kind of stain of a death within the clinical trial. And to my mind, given that there are decent alternatives in sermorelin or tesamorelin, I don't know why anyone would specifically select CJC-1295 until all these safety issues have been resolved. I'd like to take a quick break to acknowledge our sponsor, Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means zero sugar and the appropriate ratios of the electrolytes, sodium, magnesium, and potassium. And that correct ratio of electrolytes is extremely important because every cell in your body, but especially your nerve cells, your neurons, relies on electrolytes in order to function properly. So when you're well hydrated and you have the appropriate amount of electrolytes in your system, your mental functioning and your physical functioning is improved. I drink one packet of Element dissolved in about 16 to 32 oz of water when I wake up in the morning, as well as while I exercise, and if I've sweat a lot during that exercise, I often will drink a third Element packet dissolved in about 32 oz of water after I exercise. Element comes in a variety of different flavors, all of which I find really tasty. I like the citrus, I like the watermelon, I like the raspberry. Frankly, I can't pick just one. It also comes in chocolate and chocolate mint, which I find taste best if they are put into water, dissolved, and then heated up. I tend to do that in the winter months because, of course, you don't just need hydration on hot days and in the summer and spring months, but also in the winter when the temperatures are cold and the environment tends to be dry. If you'd like to try Element, you can go to drinkelement, spelled lmn t.com/huberman, to try a free sample pack. Again, that's drinkelement.com/huberman. Okay, so there are definitely other synthetic growth hormone releasing hormone peptides that are out there, but I think these three that we've covered, sermorelin, tesamorelin, and then CJC-1295, account for the vast majority of those that I put into category one. The other category, which I'm going to call category two, you'll also hear a lot about, and they operate a little bit differently. These peptides encourage the release of growth hormone, but they do so either by mimicking or stimulating the release of another peptide called ghrelin. Some of you may be familiar with ghrelin because ghrelin is a peptide that increases in concentration when we are hungry. So, it stimulates hunger, and it also stimulates anxiety somewhat. So, you may be wondering why would anyone want to increase levels of growth hormone and ghrelin? And the reason is that the ghrelin itself can impact the growth hormone pathway pretty potently. So, you can get really robust increases in growth hormone, but because there are ghrelin increases as well, you get big increases in hunger and anxiety in some people and lesser in others. Now, the different names of the peptides in this type two category are ones that you'll hear kicked around a lot these days, things like ipamorelin. Okay, so don't get ipamorelin confused with tesamorelin, right? Tesamorelin's a type one growth hormone releasing hormone peptide. Ipamorelin is in this category two. So, it's definitely going to increase ghrelin, which is going to increase hunger. It does have certain advantages, in particular that it increases growth hormone release by two mechanisms. It increases it directly, and it tends to suppress something called somatostatin. Somatostatin is a bit of a break or an antagonist on growth hormone release. So, with ipamorelin, you're essentially removing the break on growth hormone release, allowing more growth hormone to be released such that you get a lot of growth hormone released. It also tends to really improve sleep, but again, by increasing the amount of deep sleep. We don't know whether or not it does that to at the expense of rapid eye movement sleep. So, ipamorelin is the most commonly discussed one in this type two category. The other one that you'll hear about is called Hexarelin. Hexarelin is available by prescription and it is the strongest stimulator of growth hormone release, which leads many people to think, "Okay, I want Hexarelin. That's the one that's going to give me the biggest growth hormone pulse." And indeed, the growth hormone pulses from Hexarelin can be as great as two or three times more than with the other growth hormone secreting peptides that we've talked about. However, we know that Hexarelin can also dramatically increase prolactin, which can cause suppression of libido, it can cause fluid retention, it can cause a kind of feeling of malaise, especially at high levels. And perhaps most problematically, Hexarelin can desensitize the receptors for growth hormone-releasing hormone, such that your system will no longer respond either to the Hexarelin or to any other peptide or perhaps most importantly, to any endogenous, that is, naturally made growth growth hormone, excuse me, releasing hormone that you would make. Okay? So, that's something to really consider. If you're going to explore Hexarelin, make sure, please, that you're working with a physician. Make sure that you're not taking too much of it or for too long, and keep an eye on those prolactin levels because those can be problematic if they get too high. And, you know, by my read, I can't see why anyone would use high doses of Hexarelin. Maybe low doses of Hexarelin if your doctor thinks that's what's appropriate for you, but you'd really want to avoid that receptor desensitization because you could essentially turn off the system permanently. Now, there are a bunch of other what I'm calling type two growth hormone-promoting peptides. These include GHRP-2, GHRP-3, GHRP-6. Again, different amino acid sequences all designed to achieve the same thing, which is more growth hormone. Things like GHRP-3 can potently increase growth hormone, but are known to also potently increase prolactin and cortisol, leading to more than a doubling of circulating cortisol, which, depending on how well regulated it is across the time of day, can be problematic. In other words, you want a cortisol levels pretty high in the early part of the day, but you want them very, very low in the later part of the day and at night. And keep in mind that almost always these growth hormone peptides, whether or not they're type one or type two peptides, are taken before bed, typically, you know, 20 or 30 minutes before sleep. Always it's suggested that they be taken at least an hour and a half after eating any food and that you don't eat for at least 30 minutes afterwards because if you happen to have elevated blood sugar or you've got food in your gut, they're not going to have as potent an effect at increasing growth hormone and IGF-1. So again, you want to avoid food in the hour and a half, probably 2 hours before taking them and certainly in the half hour or longer after, which is why most people take them right before going to sleep and add or augment that big growth hormone pulse that occurs in the in the early part of the night. And then many people have perhaps heard of what's called MK-677, which is simply an oral version, a non-injectable but oral version of these GHRPs. And it tends to have the same issues that the other GHRPs have, which are elevated cortisol and in some cases elevated prolactin as well. Okay, so if we just going to zoom out from all this, we can say that yes, indeed, there are synthetic peptides that can potently increase growth hormone and IGF-1. I explained the rationale for why people would want that or perhaps to explore that. I'm certainly not suggesting anyone do this. Again, I am suggesting that if you do explore it, you work with a board-certified physician. And that you get these compounds from a quality compounding pharmacy or by their name brand prescription. In type one, we've got sermorelin and tesamorelin. Both are FDA-approved for certain purposes. They're being used off-label for increasing growth hormone and IGF-1 for the sorts of things we're talking about here. They are taken anywhere from three times per week to five times per week. Keep in mind, tesamorelin lasts a little bit longer than sermorelin. CJC-1295 is the third in that category of type one growth hormone secreting peptides, but it may, again may, we don't know have some safety issues that still need to be resolved, making sermorelin and tesamorelin, at least to my mind, better options should you decide to go down this path. The type two growth hormone releasing peptides include things like hexarelin, which are very potent in increasing growth hormone, but can potentially increase other things as well, but of more concern is really that it can cause receptor desensitization, maybe even turn off the whole receptor pathway. That would not be good. Ipamorelin, again, increases growth hormone directly and allows more of it to be released by suppressing its brake, its natural brake, which is somatostatin. And then the GHRP-2, 3, 6, and MK-677, all of which can potently increase growth hormone, need to be considered in light of the fact that they cause big increases in cortisol, and in some cases can cause some receptor internalization or desensitization as well, although not as potently as hexarelin. So, hopefully that description clarifies some of what you've heard out there about these different compounds and their different names, etc. It can be very confusing. I did take the liberty of designating a type one and a type two category. I did that for sake of clarity because there are a lot of different acronyms and numbers, etc. that can be really confusing to people, and I hope that that will be useful in facilitating further discussions about these compounds going forward. Two additional brief but important points. Many of the peptide vendors that are out there and physicians that are working with peptides will combine different growth hormone promoting peptides. So, they'll, for instance, have sermorelin or tesamorelin in combination with hexarelin. Or they'll use ipamorelin in combination with CJC-1295. While I'm not opposed to that approach, you just want to make sure that the dosing, or I should say the relative dosing of each peptide is such that, you know, you're avoiding unnecessary increases in prolactin and cortisol, and that you're not hitting a pathway redundantly. That's actually the logic of combining different things. These different amino acid sequences, these different peptides that is, are designed to stimulate different modes of action for the same peptide. So you the naturally occurring peptide goes and does a bunch of things, those pleiotropic effects, and these different peptides that are of different amino acid sequences are designed to, you know, reduce uh visceral adiposity a bit more or promote deep sleep a bit more or to promote muscle growth a bit more. So when people are combining different things in cocktail, it's not necessarily a bad thing, but you want to make sure that you're working with someone who's very familiar with peptides. You know, really has been in the peptide space for a long time and understands how these things work alone and in combination. And there are some excellent physicians that are doing that. Um and we plan to have at least one of them on the Huberman Lab Podcast as a guest in the not too distant future and you can bet that this conversation will facilitate your understanding of that discussion. The second point is that there are of course risks to taking anything, but in particular to exploring augmentation of the growth hormone pathway. When people take growth hormone itself, there are common risks such as carpal tunnel syndrome. Um that has to do in part with the fact that it can potently increase cartilage growth. There can be active changes in the structure of one's head and face and body. There's a so-called um uh lean but distended gut. So people that aren't carrying a lot of uh subcutaneous fat, but that the gut becomes uh extended. Sometimes you can get changes in the face like the um you know, a a kind of a a thickening of the of the bone above the brow. You'll see that. And sometimes people will look quite different after taking growth hormone for a series of time than they did before. It can really change one's stature and and shape uh to a considerable degree. It also can create a kind of a uh kind of a a skin texture that is a little bit unnatural or unusual. You You can see this in people that take a lot of growth hormone. In general, when people take growth hormone promoting peptides, the changes in body structure are not as dramatic as when people take growth hormone itself. But, body shape changes and cosmetic changes aside, keep in mind that anytime we augment growth hormone, either by taking growth hormone directly as a synthetic compound, or by taking a peptide that increases the amount of growth hormone that we release, we are increasing our tumor growth risk and our cancer risk. And that's because growth hormone and IGF-1 are somewhat indiscriminate in terms of the tissues that they promote the growth of. So, if you have a tumor someplace and it's small, taking exogenous growth hormone or increasing the amount of growth hormone that you release by taking one of these peptides that we discussed, will increase the size of that tumor. It's very likely. And you can imagine that if you're taking a peptide to increase growth hormone and you're taking something like BPC-157, something that a lot of people are starting to do nowadays, you could potentially increase both the size and the vascularization of a given tumor. So, just keep that in mind. Just as there are anti-cancer drugs that focus on the VEGF pathway to try and discourage vascularization of tumors, there are drugs that discourage the release of growth hormone to discourage the growth of tumors. So, if you're listening to this, you might be thinking, "Well, why in the world would anybody take this stuff?" Well, people like the effects of having elevated growth hormone. They like the effects of recovering from an injury more quickly. But, there's always going to be a trade-off between potential benefit and potential risk. The one thing that we can say for these growth hormone secretagogues, sermorelin and tesamorelin in particular, is that they are FDA-approved as compounds. However, they are not approved for all the purposes that people are taking them for, such as cosmetic effects, etc. So, I'm certainly not being disparaging of people that decide to make the choice to take these compounds. That's your right entirely. But, I do think that you should be informed about the potential risks. And if you are somebody who's considering taking any of these compounds, there's certain considerations that you definitely should pay attention to. So, for instance, how old are you? If you're younger than 30, I don't know why you'd want to augment growth hormone unless you and your doctor decide that there's a clinical need or some other urgent need to do so because you're already making a lot of growth hormone. If you're older than 30 and you're interested in using these compounds, to me it stands to reason that of course you want to make sure that you don't have any tumors or cancers that you could potentially exacerbate. But in addition to that, that you really think about using the minimal effective dose and that you use perhaps even the mildest of these different compounds in order to make sure that you don't desensitize any of the receptor pathways. And of course, there is no reason why anyone should use these compounds unless they absolutely feel they need to and there's a potential benefit there. I personally, as I mentioned before, tried sermorelin for a short while. The reductions in rapid eye movement sleep were problematic enough for me that I decided to just not take it and it's not something that I've returned to except every once in a great while I might do it to augment deep sleep just a little bit. The next category of peptide effects that we're going to discuss are peptides involved in longevity. And this is actually going to be a pretty quick discussion because really the main one in this category, besides thymosin beta 4, remember thymosin beta 4 we talked about earlier, this is a peptide that's naturally released from the thymus and the thymus is a structure that depletes over time as children age. So, some people will take thymosin beta 4 as kind of a longevity agent hoping that it will increase repair of tissues, recovery from exercise, etc. But it's not really aimed at longevity per se. It's really aimed at replacing something that's present in youth and then tends to dissipate as we get older. That is the thymus and related peptides from the thymus. But the big one in the category of peptides to potentially I want to highlight potentially improve longevity is epitalon. Epitalon is also sometimes spelled and pronounced epithalon. Okay, don't ask me why. And as with BPC-157, there are quite a few animal studies exploring epithalon and its effects on various tissues as well as the naturally occurring peptide that it's meant to resemble. Epithalon is a peptide that's secreted from the pineal gland. The pineal gland is a gland that most people associate with melatonin release and that's because the cells within the pineal called pinealocytes secrete melatonin at night. It's what makes us feel sleepy and go to sleep. Melatonin is suppressed by light viewed by the eyes. There's actually a pathway that goes from the eyes into the brain. There are a couple of stages that go up through the cervical ganglion from the brainstem and up to the pineal and suppress melatonin release. Now, the pineal makes other things besides melatonin. It also makes a peptide called epithalamin. Epithalamin is a peptide that is naturally released from the pineal, especially early in life, and that's associated with various anti-inflammatory effects on other cells and tissues in the body. And it does appear to be able to adjust telomere length, which is a feature of cells that's thought to be associated with the longevity of cells or how long they live. Keep in mind that the relationship between telomeres and longevity is a controversial one. People were very excited about this some years back, then people batted down that idea showing that telomere length was not associated with longevity, especially in humans, and now it's sort of a back and forth within the field. Keep in mind that epitalon, again, also sometimes written and pronounced epithalon, is designed to mimic this naturally occurring peptide, epithalamin. Okay? So, the nomenclature can get a little bit confusing. And what you'll find is that epithalon is available as a synthetic compound. It can be obtained in clean form from compounding pharmacies. And a good number of people will use it as a longevity agent based largely on animal data that it can suppress tumor growth, it can increase telomere length, and to some extent that it can recalibrate the circadian rhythm changes and the disruptions in the patterns of melatonin that occur as animals and perhaps as humans age. This is an important point. The pineal gland, despite being very, very small, about the size of a pea and sitting kind of in the mid area of the brain for you aficionados, it sits, you know, kind of like right on the roof of the diencephalon. And what it does is it will release melatonin each night in darkness. It can release epithalamin. And at those times it can go and have these myriad effects on restoring the brain and body during sleep. There are other things that occur during sleep that are essential, but those are key components of the restorative features of sleep. Now, we know that as we age, the amount of melatonin that we release is decreased such that if you look in babies and teens, etc., melatonin levels are very, very high compared to people of middle age and of elderly age. Likewise, epithalamin levels decrease with time. And as a consequence, markers of tissue inflammation also increase as we age because you're sort of removing this anti-inflammatory compound that's released each night. Now, there are a bunch of theories as to why the pineal regresses with age. There's some kind of wild ones about fluoride and a depletion of the of the pineal. I'll do a whole episode on the pineal at some point and we'll explore that. Some of them are very niche, some of them are frankly completely false, and others have some merit and are starting to um gain some data within the standard scientific community. The overall point here about peptides for longevity can be summarized very easily. The logic is just as we have a thymus early in life, the thymus secretes certain things, and those things seem to accelerate robust tissue healing early in life. And as the thymus disappears, tissue healing gets less robust. That's the logic for taking things like thymosin beta-4, TB-500. So, too, we have a tissue, the pineal, that secretes certain things early in life that are associated with lots of deep sleep and robust tissue repair and long cellular life. The logic then is by taking epithalamin you can mimic this peptide that's normally released from a nice young healthy pineal and in that sense encourage anti-inflammation pathways as well as cellular longevity pathways. That's the basic idea and again it rests largely on the animal data for which yes, there's some interesting studies showing suppression of age-related ocular diseases. There's some nice studies showing telomere expansion. There's some nice studies showing that several features of brain aging and body aging can indeed be partially offset by things like epithalamin peptides, but it is indeed a leap that people are taking when they are deciding or taking epithalamin in order to extend their life, right? It's the logic is all there, but the pieces are sort of cludged together between what we know about the animal studies, what we know about the naturally occurring compounds that these peptides are designed to mimic and yet there are still no clinical trials that point directly to taking x amount of epithalamin several times per week as a way to extend life. The fourth and final category of peptide effects that we're going to talk about are effects on vitality, both mood and libido. And really the main players within this category of peptides are the so-called melanocyte stimulating hormone-related peptides. Okay? Just to give you a little bit of background. Remember the pituitary? The pituitary gland, that stalk that extends out of the brain and can release growth hormone from the anterior pituitary. Well, it's got a middle segment or a medial segment and there's a hormone that's released from there called melanocyte stimulating hormone. Melanocyte stimulating hormone has the effect of stimulating pigmentation of the skin by activating what are called melanocytes that exist within the skin. So the peptides, melanotan 1, melanotan 2, melanotan 3, melanotan 4, melanotan 5, because there are five of them, are different peptides, that is, peptides with different amino acid sequences, all of which mimic naturally occurring melanocyte-stimulating hormone, but that act preferentially on one set of melanocyte-stimulating hormone receptors or another in order to get different effects. So, let's back up a little bit and talk about the melanocortin system, right? The melanocortin system is a system whereby viewing light or getting light on the skin, typically ultraviolet light of the ultraviolet B type. Okay, there's two different types of ultraviolet light, but basically sunlight is what the system evolved to respond to, shown to the eyes and or to the skin stimulates the melanocortin system. It goes from the eyes to the hypothalamus, from the hypothalamus to the pituitary, and then the melanocyte-stimulating hormone is then released into the bloodstream, can travel to the melanocytes, and cause pigmentation of the skin. This is what is responsible for tanning. There's also a pathway whereby the light stimulates the melanocyte-stimulating hormone system, and in parallel stimulates the release of dopamine. Now, for any of you that have lived in a part of the world in which it's very, very dark with very short days in the winter and longer days and a lot of sunlight during the summer, you're probably familiar with the fact that when the sun comes out, people start feeling better. They have more energy, they're more motivated, a number of different systems related to mood and libido tend to increase. This is the consequence of sunlight activating the melanocortico system. And by the way, this system is very active in other animals as well. Animals that are white or tend to be of pale color during the winter, then as spring arrives, the sunlight stimulates this very same system and leads to darkening of the pelage, so their hair goes from white or gray to brown or even dark black or some combination of those and in combination dopamine is increased, libido is increased and the animals start breeding in the spring and summer months. Okay, so this is a a well conserved system across species and it exists to some extent in us as well. So there are essentially five different synthetic peptides called melanotan 1 2 3 4 and 5. Each of which is designed to mimic melanocyte stimulating hormone but each of which activates different receptors to different degrees and some can cross the blood-brain barrier and some can't and as a consequence some impact mood and libido and others don't. The simple way to look at this is that melanotan 1 does not cross the blood-brain barrier. It does however stimulate the melanocytes of the skin, so it leads to tanning or darkening of the skin. Melanotan 2 3 4 and 5 also lead to darkening of the skin by way of activating melanocytes in the skin but because they can cross the blood-brain barrier they cause effects that are at the level of psychology, really, and at the level of appetite and things of that sort. In general the pattern is to increase mood and libido and to decrease appetite. Things are associated with the transition from winter to spring and summer months in humans and in other animals. Now one of the things about the peptide literature is that it loves acronyms and numbers and so there's a peptide PT-141 that falls into this category of activating the melanocortin system. And PT-141 is also known as the prescription drug Vyleesi. PT-141 or Vyleesi is FDA approved for the treatment of premenopausal hypoactive sexual desire. So this is FDA approved for the treatment of women that have suppressed libido. However men also will take Vyleesi for hypoactive sexual desire. This is obviously prescribed off-label um physicians, but keep in mind as with the other peptides in this pathway, Vyleesi will stimulate pigmentation. So, whether or not you consider that a side effect or a benefit depends on, I guess, your baseline level of pigmentation and how much level of pigmentation you actually want. Now, there are some side effects associated with these compounds. Uh one of the more common ones is nausea, and that's because there are melanocyte stimulating um hormone receptors all throughout the gut. They can also cause flushing of the skin, and they can cause blood pressure to increase. Also, folks with melanoma should be very cautious about using any of the peptides that stimulate melanocytes because that could potentially exacerbate melanoma. The next peptide in this category of peptides for vitality and libido is kisspeptin. Kisspeptin is a peptide that wasn't discovered that long ago. I actually can recall when the first papers about kisspeptin came out. And basically, kisspeptin is a peptide that is naturally made within the brain, and it's upstream of some of the hypothalamic signals that activate the pituitary for sake of hormone production and reproduction. So, I'll just walk you through this pathway. It's actually quite simple. You've got the pituitary. You're now familiar with the pituitary, and the pituitary releases two different hormones in both males and females. It releases luteinizing hormone, and it releases follicle-stimulating hormone. If you watched the episodes that we did about testosterone and estrogen, if you watched the episode that I did on male and female fertility, if you watched the episode that I did with Dr. Michael Eisenberg from Stanford or Dr. Natalie Crawford, who's an OBGYN uh specializing in fertility, we talked a lot about LH and FSH. Basically, FSH, as the name suggests, stimulates the growth of the follicle, the egg in the female, and it stimulates sperm production in males. Luteinizing hormone stimulates testosterone production from the gonad in males, and it also stimulates estrogen production, and to some extent, testosterone production in females as well. So, we need LH and FSH to stimulate the gonads, the ovary or the testes. The hormone that stimulates LH and FSH release is called GnRH or gonadotropin releasing hormone, and it comes from the hypothalamus. So, GnRH is a signal that promotes LH and FSH release. Now, that raises the question, what turns on GnRH? And the signal that turns on GnRH is kisspeptin. Kisspeptin, in other words, is further upstream from GnRH and LSH and FSH. It's a cascade. It goes kisspeptin, GnRH, LH, FSH, testosterone, estrogen. Okay, that's the pathway. Now, it's very clear that kisspeptin is involved in the activation of puberty, the transition from pre-pubertal to post-pubertal stages of life. It's also involved in any of the sort of downstream effects of having elevated LH and FSH, including elevated vitality, which includes both energy and in some cases libido. So, there's naturally occurring kisspeptin, and there's now synthetically generated kisspeptin designed to mimic naturally occurring kisspeptin, and it's actually prescribed for what's called hypothalamic amenorrhea. Hypothalamic amenorrhea is the loss or the absence of periods of menstrual cycles that are the consequence of deficits within the hypothalamus itself. So, not something within the ovary or a lack of the pituitary to make LH or FSH, but a deficit of the hypothalamus to promote LH and FSH and the downstream hormones testosterone and estrogen. Incidentally, there are also kisspeptin antagonists, okay, drugs that are designed to suppress kisspeptin, and those are used to treat some of the symptoms of menopause, including night sweats and some of the what are called vasomotor symptoms. So, kisspeptin is obviously a key player in this whole pathway of steroid hormone release, the steroid hormones being testosterone and estrogen. There are other steroid hormones as well, of course. Now, there are folks within the landscape of peptide therapeutics, folks meaning physicians and other practitioners, who said, "Oh, well, here's a a peptide that is known to promote all these hormone pathways that are associated with vitality, libido, etc." And so, there are people who take kisspeptin peptides as a way to stimulate these pathways, and they're doing so for the specific purpose of increasing vitality as it relates to libido and mood and to get the downstream increases on testosterone and estrogen. And of course, some people are taking kisspeptin peptides to treat hypothalamic amenorrhea. And as I mentioned, some people are taking kisspeptin antagonists. They're trying to block the kisspeptin pathway in order to reduce some of the vasomotor and other symptoms of menopause. I will say despite the fact that the kisspeptin pathway is well known, and despite the fact that the kisspeptin peptide is designed to mimic a naturally occurring peptide that has a pretty constrained set of functions in the hypothalamic pituitary system and their downstream effects on the gonads, the use of kisspeptin to increase vitality and libido is a bit of a um let's just say it's a it's a little bit of a wild card. We don't yet know all the effects of kisspeptin. Again, it was fairly recently discovered. We have it in mind that it's involved in these pathways, but I should say every time we look at a given peptide, whether or not it's ghrelin or hypocretin orexin or it's GLP-1, what we find is that again, there are these pleiotropic effects. There is rarely, if ever, one specific effect. And it's not just a concern about side effects that we want to take these pleiotropic effects into consideration. It's the fact that even though we know a lot about the human body and the various hormones and neuromodulators like dopamine, serotonin, etc. that are made, this landscape of peptides is an enormous one, and it's one for which we are just now really starting to appreciate how many different peptides the human body and brain make. Again, I don't think it's an overestimate to say that there are probably hundreds of thousands of different peptides, each with multiple and sometimes even overlapping and synergistic effects. So, I do understand the excitement about peptide therapeutics. I think for a lot of people that want to improve their physical health and mental health, they want to recover from injuries more quickly. Maybe they're seeking particular aesthetic changes or mood changes, et cetera. I understand the gravitational pull and the excitement of peptides, but I have noticed that the discussion around peptides, because it's in contrast often to the discussion around hormone therapies like testosterone therapy and estrogen therapy, people, I think, inadvertently assume that peptides are all safe or innocuous, or that they are potent enough to do certain things that we want, but that because they're not hormone therapies per se, that they are free of side effects and risk. And in addition to wanting to teach you about some of the biology of these peptides and how they work and what they're designed to do, as well as some of their potential therapeutic benefits under the right conditions, again, working with a really good board-certified physician and making sure that the sourcing is really clean and that you're doing regular blood testing and you're monitoring for any potential tumor growth, et cetera. I also want to emphasize that these are very potent compounds. They have lots of different effects, and we are in the early stages of exploring peptide therapeutics. Again, I'm not here to tell you what to do or what not to do, but if you have it in mind that peptide therapeutics, because they aren't hormone therapies, are not without their potential risks, you would be wrong. All of that said, it's very exciting to see what's happening with peptide therapeutics. I'm excited about their potential for both the treatment of disease as well as for augmentation of mental and physical health, and I think it's an exciting landscape that certainly motivated uh my desire to do this episode and get you familiar with them, or at least with some of them. And it's something that we're definitely going to be exploring more on this podcast, both with expert guests and in solo episodes going forward. If you're learning from and are enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. 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