AMA Host or Interviewer (3:31)

Peter, welcome to another ama. How are you doing?

Peter Attia (3:34)

I'm doing great man. How are you?

AMA Host or Interviewer (3:36)

I'm doing good. For today's ama, we are going to be talking about peptides. So peptides are a topic that we get asked about an insane amount. You see so much content on there. Even today going through our email inbox, we had two emails asking us to talk about peptides. So it's a topic we see over and over. And our goal with this episode is not to promote dismiss peptides overall, but just to give people a framework and how to think about them. Which is what are peptides? Where is the science solid, weak or non existent? And how to evaluate the claims that people make. With this we'll walk through a core set of questions that apply to any peptide and we'll apply it to a variety of peptides to kind of walk through some of the most popular ones, which is whether we know there's a mechanism of action, what do we know about safety and dosing, Is there any evidence that it can be helpful in humans? How do someone compare the risks and the potential benefits and are there any other legitimate approved solutions that are available? And then at the end we'll also zoom out and talk about the gray market space for peptides, including how people should think about purity, sourcing, etc. And then we will truly end on the potential future of peptides and what we would need to know, what new information would have to come out to really understand where these could be promising. A lot to cover, a lot of different things we said. Anything you want people to know before we get rolling?

Peter Attia (5:11)

No, I think you've covered it. I don't think there's a topic I get asked about more today and probably for the last six months than this topic. I would just add that the reason it has taken us so long to come out with this AMA is we wanted to do this justice. We don't do anything in moderation on this podcast except for moderation There's a bar that just had to be cleared. I hope we're about to clear it for you as a listener. And it just took. I'm actually kind of afraid to ask how much time it took of our research team to help me get ready for this. So let's dive into it.

AMA Host or Interviewer (5:49)

Perfect. I think we got to start off with defining what are peptides, by the

Peter Attia (5:54)

way, it's funny, my wife asked me this over the weekend. We were sitting there, she was asking me a peptide question and it was like we were having dinner with the whole family. And of course, naturally the 8 year old and the 11 year old are like, what are peptides? And so I'm explaining to them what peptides are in anticipation of this discussion. So look, there's nothing magical here. A peptide, it gets talked about in this health and wellness space like it's something magical or new, but it's not. A peptide is a short chain of amino acids. I don't think there's a real clear definition of what constitutes a peptide versus a protein. Clearly, once you're into the thousands of peptides, you're clearly talking about proteins. I would say. I've read definitions that would suggest up to 60, up to 100, I don't know. But the point is it's pretty small. So a short number, relatively short number of amino acids strung together forms a peptide. Now, by the way, sometimes it's so short that it's literally just a straight line of amino acids. And other times they form more complex structures, they form rings and things like that. Again, these are things that the body naturally produces. So there are many peptides that are produced naturally. They serve all sorts of essential functions. They act as signaling molecules, neurotransmitters. They act to facilitate the transport of molecules. They sometimes can act as antioxidants. So some of these peptides are going to sound really familiar. Some of the most important things that people have heard of, like endorphins, insulin, GLP1, these are all peptide hormones. Now of course, some of these things can be produced synthetically. So we're able to create peptide based therapies that can mimic the endogenous or body produced peptides. So again, I would say here the single most important of these would be insulin. Insulin was discovered roughly a hundred years ago and it was clear that in a disease called type 1 diabetes, that people who lacked insulin because their beta cells were being attacked by their immune system were going to die. And if we couldn't give them some form of insulin, and initially that was done by taking insulin from dogs or pigs that they were going to be in trouble. But ultimately, of course, once insulin could be synthetically produced, you could create a therapy to save the life of somebody

Peter Attia (8:08)

with type 1 diabetes.

Peter Attia (8:10)

More recently, of course, people will be very familiar with the GLP1s. We're going to talk about that because in the GLP1 world, we're not typically giving people the exact same peptide, but we'll come back to that. So anyway, that's maybe more than you want to hear, but we'll start with

Peter Attia (8:25)

that as a definition.

AMA Host or Interviewer (8:26)

It's good for people to hear how many different molecules the word peptides can cover. But I think a lot of times when people are asking questions about peptide supplements, traditionally it seems like they're not always referring to insulin or even GLPs. And so for the sake of this conversation today and not having 18 hours to go over everything, what is your goal with the peptides you want to make sure we talk about today?

Peter Attia (8:51)

Well, it's interesting. We're going to actually talk about these a little differently. So we're definitely not going to talk about insulin today. We will talk a little bit about GLP1, but from a sort of regulatory standpoint, in medical terms, I would say a peptide broadly refers to an FDA approved therapeutic molecule, again like insulin or GLP1 drugs. But I think in the more colloquial sense, the word peptide as we are going to talk about it today is more of the bio hacking pop science bro science connotation that refers to various therapeutics that are touted for various benefits, often related to, quote, longevity and beauty and tissue healing, recovery performance, but they don't have an FDA approval at all or they're being just used off label

Peter Attia (9:40)

for any of these purposes.

Peter Attia (9:41)

So when we're going to talk about peptides, we're going to be talking about things that are generally administered via injection that have become popular despite a lack of scientific or medical consensus on their efficacy. These are going to be things that are virtually all available through gray market means. And again, we're going to talk about what that actually means and why that's necessary. By necessary I mean why that's the means by which you would acquire these things in which their sale isn't technically illegal, but by marketing them for, quote, research use only, and I'm being very clear in that language, they're not approved for human use, but everybody understands that they are indeed being used by people.

AMA Host or Interviewer (10:25)

Yeah. And given that a lot of these are gray market, not FDA approved peptides how do you recommend people start to think about them and start to evaluate the potential of whether they can be helpful or not?

Peter Attia (10:38)

I think we want to talk about this across the entire spectrum of efficacy and safety, but I don't think we want to even entertain the question, do peptides work as a category? The answer is, obviously they do. Again, we'll point to GLP1 agonists, insulin, and even longer proteins that are probably on the verge of still being peptides like HCG that are clearly clinically efficacious. So I think what we want to really do is take an unbiased approach and evaluate whether any given peptide has enough evidence for its safety and its actual efficacy and examine the regulatory structure of it and ask the question, is there a justification for real world use? And again, I think this is most helpful when evaluating things through the lens of these unregulated peptides. And that's really where we're going to focus today. That's the value I think we can bring in this podcast to this discussion. So, again, whether you're FDA approved or not, I think you should always be asking the same question of anything you put in your body. Let's just take a few steps back and not even think about this through the lens of a peptide. If you're gonna put any drug in your body, you should be asking these questions, and the answers to these questions should be kind of informing your decision making. So the first question is, is there a viable mechanism of action? There's very technical ways to think about this. I'm not interested in vague theories like, oh, it boosts energy production. That's not a mechanism of action. What we want to know is, do we have a defined course of mechanistic steps that might logically lead to an intended effect? So this is very important. In fact, the list of drugs that are approved by the FDA for which we don't have a mechanism of action is very small. It's estimated to be no more than 3% of total drugs that are approved. And this includes over the counter drugs. If there's no mechanism of action, you should be very skeptical of a drug or supplement. This is everything that you get a prescription for and everything that is sold legally over the counter. Less than 3% of these. We don't understand the mechanism of action. Now, there are some interesting examples. So Tylenol is an exception. Believe it or not, we don't actually know how Tylenol works. We don't know how lithium works. You know, we did a newsletter on this somewhat recently talking about lithium for potential cognitive benefits. We don't actually know how it works. There's some speculation, but we don't know something like Mucinex. We don't really know how that works. So there are exceptions out there, but they're very rare. Another question you should be asking is what do we know about the downstream effects of this in healthy individuals? That is the intended effect. So this is another way of saying what is the efficacy of this drug in particular in healthy humans or in the patient population that we're interested in addressing this in? Of course, another question is what do we know about safety? And that usually means starting in animals, but eventually you have to figure out what the safety looks like in humans. And of course that's also a function of dose and usage pattern. How do you put these things together? Well, how do you then weigh the potential risks of the potential side effects with the intended benefits of the drug? Take something like an antibiotic. Antibiotics have lots of side effects. Some of them can be really quite devastating. But we also know that they have really important intended downstream effects. As such, nobody would ever suggest you just take antibiotics, willy nilly. That would not make sense to ward off any potential bacteria in the room. Rather we reserve them for when the risk of not taking the antibiotic is high enough. Another question I think we always want to be asking is are there legitimate approved alternatives available? This is actually specific to the peptide question because again, once you start to talk about things that are gray market, where you have no way of scrutinizing the legitimacy of a compound, you have to ask yourself, well, if I'm going to take this, should I be at least considering something that is FDA approved that might have the same risk and benefit profile? Once you answer all of these questions, you can put any one of these peptides into basically a group of buckets. You know me, I love my frameworks. So this is kind of a framework that we've come up with that I think you could put any peptide into. And there's four buckets. So bucket one will be, you've gone through this line of inquiry and you really can't make a compelling case for it. If you're being honest, you can be dishonest and come up with compelling cases for anything. But if you're being honest, intellectually honest, there would be no use case for this peptide. So these would be things for which you have no viable mechanism of action. You just don't have data or there's some theoretical mechanism, or there's existing data that actually refute it. You don't have any data in humans or you might even have negative data in humans. Another thing to look for with these peptides is when you get a lot of shifting goalposts for the alleged benefits. These are peptides where they tout one set of benefits and then they a couple of years later come out with a new set of benefits and then a new set of benefits and they're just kind of making up a new

Peter Attia (16:12)

story all the time.

Peter Attia (16:12)

Then you have your bucket two peptides. Here you have a viable mechanism. But the compound has never entered clinical trials or if it did enter human clinical trials, it was abandoned. There's no real continued interest from pharma. So we're going to talk about some examples there. Your bucket three peptides have a viable mechanism of action. They might even be currently in human clinical trials. They might even be approved for indications other than those that are intended in the general use population. You do have safety and efficacy data, though not necessarily in the population you're interested in or for the indication you're interested in. But they don't have an approved version that exists for the current popular use. And we're going to talk about examples in all of these. Finally, the fourth bucket. These are basically peptides that are stolen FDA approved drugs or hormones. So they're basically peptides that are being sold that are being touted as exact replicas of approved drugs, but they're being sold illegally via research purposes only. So we're going to talk through a handful of examples in a lot of detail to sort of a cover those peptides because these are very popular ones, that's why we've chosen them, but also to kind of lay out the thinking that we'd like you to do as you embark on this journey yourself. I'll point out that in the show notes we're also going to include kind of a database we've put together of, I would say, oh, I don't even know, I've lost track, maybe 20 other peptides that we've come up with our

Peter Attia (17:47)

own point of view on.

Peter Attia (17:48)

Okay, so what are the ones we're going to start on? We're going to kind of go a little deep into the following SS31, Melanotan to CJC 1295 and BPC 157. Why did we pick those four? They're incredibly popular. They're probably the ones I get asked about the most from patients, friends, anybody. And our goal is to evaluate them through the lens of these questions. We just laid out what are the clinical claims, what's the evidence, what are the risks, what are the practical considerations, etc. So hopefully this gives you sort of a framework to evaluate any other peptide, including the ones that we will cover later on. We're then going to talk about these corporations questions, the gray market peptides, and talk about how these things are subject to some regulatory oversight, et cetera. Let's just dive into it.

AMA Host or Interviewer (18:39)

Let's do it. Let's start with the first one. SS31 let's start with the question is there a viable mechanism of action that

Peter Attia (18:47)

we know for thank you for listening

Peter Attia (18:50)

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Peter Attia (19:14)

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Peter Attia (19:15)

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