#403 ‒ Peptides: separating scientific promise from marketing hype

Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. This podcast, my website and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com/subscribe. Welcome to another episode of the Drive. Today we are returning to the topic of peptides. You might ask why? Well, it's a topic surrounded by a lot of misinformation, so we wanted to put out a concise version that's actually going to be accessible to everyone. We're making the original AMA and the show notes, which were done several months ago, free to everyone as well. For anyone who wants the fuller more detailed treatment, you can go back to that one, but otherwise this is going to be hopefully a one-stop shop. This is a topic I get asked about more than almost anything else right now, and I suppose for good reason. Peptides sort of sit at the intersection of what might be described as real biological promise, genuine clinical wins, and rampant commercialization. They get marketed as cutting edge regenerative therapies for everything, from muscle repair to "longjevity" to looking better on the beach. I would say one of the reasons I wanted to make this episode is that I completely understand why people are drawn to peptides. If you're in pain, if you're injured, if you're aging, if you're exhausted, frustrated, the promise of something that accelerates healing and restores your body is almost impossible to ignore. I don't think that most people using these compounds are reckless. I think they're hopeful. My concern is that hope has become a product. It's being sold by attaching extraordinary claims to molecules that in many cases have never earned such claims. So the goal today isn't to promote peptides or to dismiss them outright as a category. It's to hand you a framework because you know me and you know how much I love frameworks for thinking about any peptide you come across, what it is, where the science is solid, where it's weak, and where it's simply absent. We'll run through that framework with an example, and then we'll zoom out to the gray market, sourcing, and where the field is headed. Ultimately, you should leave with a framework for deciding when the answer is yes, when the answer is no, and when the honest answer is that the evidence simply isn't there. So without further delay, please enjoy this episode of The Drive. So Peter, I think as we get started, it'd be really helpful to first define what peptides are. Right? So a lot of people use the term, and so what does it mean when we say peptides? And ultimately, what is your response if someone comes to you and asks, "Hey Peter, should I be taking peptides?" Well, when people ask me about whether peptides work, my first response is usually some variation on you're asking the wrong question. That's sort of like asking whether drugs work or whether surgery works. A peptide is simply a short chain of amino acids. Some of these are among the most important drugs ever developed, like insulin, and of course, the now ubiquitously used GLP1 agonists, while others have essentially no credible evidence behind them. The word tells you almost nothing about whether a molecule is safe, effective, or even scientifically plausible. It's a chemical description, not a mark of quality, and one of the biggest marketing successes of the last decade has been convincing people otherwise. Distilling this increase in a singular group of molecules down into a single word does a significant amount of rhetorical heavy lifting. Peptide conveys sort of a naturalistic connotation, essentially conveying that it is safe and effective by default. But these are drugs, and even if you bought into the natural is better argument, most of what you're buying is synthetic, deliberately modified versions of natural molecules engineered to bind to a receptor more tightly, to last longer in the body, or to hit a target the original protein or peptide never could. So rather than ask one simple question, whether peptides work, we actually need to be asking multiple specific questions about individual peptides. And so Peter, let's double click on that. So when people are looking to evaluate these individual peptides, what questions do you think are the most helpful for them and why are they so important to be able to answer? Well, in our original AMA on peptides, which was released in April of this year, we outlined a framework with which we evaluated many of the most popular peptides. Here's what I like about this framework. It does its best to remove personal bias by forcing you to ask the same questions of drugs that you believe are good as drugs or don't or are frankly indifferent about. And it works for any drug, not just the category of drugs known as peptides. So if you're putting something into your body, I think these are the questions worth asking. First, is there a viable mechanism of action? A real mechanism of action forces the claim to become falsifiable. It asks, what is the molecular target? What changes downstream? And why would that plausibly produce the clinical effect being claimed? Without that chain, a claim like it boosts energy or supports immunity or reduces inflammation can mean almost anything and almost certainly nothing. It becomes marketing language, not biology. The other reason is that mechanism helps identify failure modes. A molecule may bind the intended target, but not reach the relevant tissue. It may affect the pathway only at concentrations far above what humans could otherwise safely ingest. It may move a biomarker without affecting a disease process or it may have opposing downstream effects that erase or even reverse the expected benefit. A defined mechanism gives you a place to interrogate the claim. Unknown mechanisms do exist in medicine, but they are absolutely the exception and not the rule. For example, if we look at FDA approved drugs, the share with genuinely unclear mechanisms is small. It's about 3%. So if a compound has no plausible mechanism, that should be an early red flag. Okay, the second question you want to be asking is, do we have evidence of a meaningful benefit in humans? There are plenty of examples of a molecule that we thought should work and maybe even worked in animal studies, but then failed to produce the effect in humans or frankly was outright dangerous in humans. Consider this, for example, of the compounds that clear the preclinical testing bar and enter phase one trials, roughly 30 to 50% still fail to advance to phase two, often because these drugs do not behave in humans as anticipated. All right, the third question is, do we understand safety, dosing, and pharmacokinetics? How much of this drug, in this case peptide, reaches circulation? How long does it stay active? What dose was studied? What are the short and long term risks? And as such, what do you need to monitor? This matters because it tells us whether the molecule's behavior in the body is predictable and controllable and whether there's a practical plan for using it safely, including what to watch for and how to intervene if something goes wrong. Fourth, does the likely benefit justify the risk for this person? Risk is always contextual. A serious adverse effect may be acceptable for a lethal childhood disease and yet completely unacceptable for some marginal wellness benefit. Risk only makes sense when weighed against the size and certainty of the benefit and against the risk of doing nothing. And then fifth, is there a better characterized way to get the same result? Because if there is, you have to ask yourself what you're actually gaining by reaching for the less characterized version of a drug. Is it more effective? Is it safer, easier to dose, or better suited to you as a person or is it cheaper, more available, new, or is it just more compelling marketing? If you run any peptide through these five questions, you'll often arrive at your answer. And based on those answers to the questions, how would you then start to classify or bucket the level of evidence for various peptides? So, you know, in the original AMA, Nick, we kind of talked about peptides being in four different buckets, but I've sort of paid attention to how I've been speaking with patients about this because obviously I'm being asked about it nonstop. And I've kind of defaulted it into three buckets. And that's kind of how I'll talk about it here. So bucket one is the scientifically unsupported tier. So the peptides that fall into this bucket, there's absolutely no validated mechanism. So either we have no idea where it binds or the proposed mechanism is vague or contraindicated by what we know. There's little or no credible human evidence that these work and the claims tend to drift over time without any clinical progress to justify them. Then you have bucket two. Peptides in this bucket, you know, look, it's biologically plausible that they might work, but it's not supported by any human clinical evidence. So this means that there may actually be a mechanism of action that's credible and that the drug could have even worked in animal studies and perhaps even does something real at the level of human biology. But there's little evidence that it improves an outcome. Right. And that's what matters in humans, especially for obviously off label goals that people are typically using these things for. These are often drugs where development has stalled or even halted because it didn't work well enough. It wasn't safe enough or perhaps it got beaten by a better drug in the pipeline. And then you have bucket three and these are kind of scientifically legitimate molecules. Now this makes it tricky because this is also the category where people often confuse a legitimate molecule with a legitimate product. I'm going to say more on that later, but these are the peptides that most likely are going to produce some biologically meaningful effect. One subtle but important point is that a drug isn't simply evidence-based. It's evidence-based for a particular dose, route of administration, patient population, indication, and clinical end point. So evidence doesn't automatically travel with the molecule. It belongs to a very specific clinical question. A drug shown to work in one disease, one population, or one dose cannot obviously be assumed to work equally well when any of those conditions change. Being in bucket three is not an endorsement. There's much more nuance to this. It means that the underlying molecule has the strongest scientific footing of the three, but it doesn't automatically mean it's safe or that the off label use helps for the indication that you might want to take it for, or even that the risk benefit calculation works for you, especially if you purchase it on the gray market. So the practical conclusions I would say differ by bucket. In bucket one, I think it's safe to say there is not enough scientific foundation to justify use. In bucket two, the biology may be real, but the claimed clinical benefit has not been demonstrated or the potential harm that arises from using it would probably lead someone like a company that's developing it to abandon it. The development history on many of the peptides in this bucket should probably temper your enthusiasm. Bucket three, the most reasonable approach is to use the product with the strongest characterization and oversight. You should be clear about what, if anything, you're gaining by using a less characterized version of that peptide. What risks you're accepting or willing to accept by substituting it for the more well-studied drug. We'll come back to this in a bit more detail later. Peter, I think what would be most helpful is if we run the framework you described with an actual peptide. I think it'd make the most sense to do one of the most prominent examples, which is what we get asked about the most, which is BPC157. Do you want to talk about what that is and then where do you land in the framework that was discussed previously? Sure. BPC157 is actually the case study and poster child for everything that should make you skeptical of a peptide. But I'm not asking you to accept this just because I've said it. The whole point of the framework is to make the case step by step. So let's run BPC157 through the framework. First, is there a clear, biologically viable mechanism? No. BPC157 is described as a fragment of naturally occurring gastric body protection compound. But its origin story is unusually murky. The alleged parent protein has never been fully characterized. And BPC157 itself doesn't clearly match any known human gastrointestinal peptide or any other human protein. When asked why the full protein sequence has never been published, the scientist who discovered BPC157 said, "If you have your own child, you want it to be yours forever." Okay? He has also refused to disclose the screening method used to originally identify the compound. So this isn't just a case of missing data. The details appear to be deliberately withheld. This is basically the scientific equivalent of trust me, bro. Now, several mechanisms have been proposed, particularly effects involving VEDGEF, vascular endothelial growth factor, angiogenesis, nitric oxide, and neurotransmitter systems. But none of those have been established in humans. And we do not know the receptor or target through which the drug principally operates. Now, I've heard people defend BPC157 as a peptide without a receptor, leaning on the fact that some drugs genuinely do not work through receptors. That part is true, but that is the slight of hand. You see, lacking a receptor is different from lacking a mechanism. A molecule can act without a classic receptor and still have a well-defined mechanism of action. And most that end up showing clinical benefit do have that. With BPC157, we do not have a clear mechanism as well. Okay, so what's the second question? Is there evidence of meaningful benefit in humans? No. Nearly everything we quote-unquote "no" comes from animal models. The positive literature is overwhelmingly preclinical. More than 80% of the published work comes from one academic group and researchers associated with that work have IP and commercial interests connected to the molecule. That does not automatically make the findings false, but it should raise the bar for independent replication. And that replication is astonishingly thin. Despite approximately three decades of claims, there are no published peer-reviewed human randomized trials demonstrating that BPC157 accelerates healing. Three decades dozens of fantastical benefits and not a single human RCT. Okay, third, do we understand safety, dosing, and pharmacokinetics? No, on all three. Human pharmacokinetics and bioavailability are unknown. So commonly promoted dosing protocols are essentially guesses. We do not know how much reaches circulation, how long it stays active in humans, what dose works, for what indication, and what the long-term risks are, or what would even need to be monitored should you care. The absence of an obvious safety signal is not evidence of safety. Phase one clinical trials to pick up safety signals haven't been run. Long-term and repeated dose effects have not been adequately studied. A practical safety framework should tell us how to use the molecule safety, what to watch for, and how to intervene if something goes wrong. But BPC157 doesn't give us any of that. Well, here's the irony. If you actually believe the proposed mechanisms, you should be worried more and not less. Pro-angiogenic Vegef and nitric oxide signaling are exactly the kinds of pathways that potentiate tumor biology. Abnormal vascular growth and tissue remodeling. Of course, that doesn't prove that BPC157 causes cancer, and I'm not saying that. But if proponents claim that it meaningfully stimulates healing through those pathways, they should also take seriously the possibility of stimulating biology you may not want over-stimulated. So the trade-off is poor, an unquantified benefit for injury, recovery, pain, inflammation, gut health, or performance against an incompletely characterized molecule with unknown dosing, unknown human exposure, limited long-term safety data, and biologically plausible cancer-related concerns. That's just not a trade I think most rational individuals would make. Fifth, is there a better characterized way to get the same result? Well, for BPC157, PC157, you do not need a perfect named alternative to reject it. You're being asked to take an uncharacterized molecule on faith. For tendon injuries, ligament injuries, pain, inflammation, gut symptoms, or recovery, there are better characterized ways to evaluate and manage the specific underlying problem. They may be less exciting, slower, less marketable, but they come with clearer dosing, clearer risks, clearer monitoring, and a stronger evidentiary foundation. BPC157 is not being chosen because it has demonstrated superior human outcomes. It's being chosen because the story is compelling. So where does BPC157 land? I think it lands very clearly in bucket one. There is not enough scientific foundation to justify its use. And you talked about how we don't know the mechanism for that peptide. Is there any chance based on the general claims around BPC157 that could suggest that it actually has a broad mechanism rather than kind of being a warning sign like you called out? I mean, look, you can never be absolute in biology, right? It's not mathematics. But I would say the answer to that question is no. And the chance of what you described is about as close to zero as it gets. A drug can have broad effects, but only when it hits a fundamental pathway, and it earns that breath. So let's look at GLP1 agonists. They didn't arrive, striving to fix diabetes, obesity, heart disease, kidney disease, fatty liver, sleep apnea, and neurodegenerative disease all in one shot. They got one indication, proved it in rigorous trials, and then over years, as real evidence came in, they earned additional ones. BPC157 has done the exact opposite. They purported benefits and have expanded while the first claim was never nailed down. Woon healing became tendons, then ligaments, then muscle, then gut disease, then inflammation, pain, performance recovery, even multiple sclerosis. It's not a new drug earning indications. That's a peptide getting repositioned across every therapeutic area imaginable with nothing rigorous to show for a single human disorder. And here's the part that bothers me more than the missing data itself. Human randomized trials are possible. Yet they're not happening. Or they're happening and the full results are never published. Someone is choosing not to look, or choosing not to tell you what they found. There's a pattern here, and it's a reliable one. Legitimate drug development narrows uncertainty over time. Bad science, or no science, expands its claims instead. And that's a very important distinction. BPC157 has been on the second track for decades. We still don't know its primary target. We still don't have a convincing human trial. We still don't know the dose or basic pharmacokinetics in humans. And somehow the list of things it treats keeps growing. This is not a signature of a broad mechanism. That's the signature of a great marketing campaign based on hype and hope. At best, nobody has bothered to actually rigorously test this thing. At worst, somebody did and didn't like what they found. And so now that you've covered why you'd be skeptical of a peptide with an unclear mechanism and no real meaningful clinical evidence, how do you feel about a peptide with, let's say, plausible biology and real biological activity? So even if the clinical outcome evidence might still be limited, does those things change how you feel about it? Well, you know, I'd calibrate enthusiasm to the strength of the evidence. And usually I'm not overly enthusiastic about peptides in this category. So I would say CJC1295 is a useful example because it is both biologically plausible and biologically active. And it's also for what it's worth probably one of the three or four peptides I could ask about the most. So I think it makes for a good illustration. Now again, we've covered this in much greater detail in the previous AMA if you want to go back and get really into the weeds of the history of this peptide and all those other things. And suffice it to say CJC1295 can raise growth hormone and IGF1. But one of the biggest mistakes people make is assuming that's because a molecule changes biology and therefore it's going to improve health. Almost every drug we study changes biology in some way. If it binds to a receptor, alters a signaling pathway, raises one biomarker, lowers another or changes the expression of a protein, that's changing biology. That's not the relevant question. The question is whether or not those biological changes translate into outcomes that actually matter to patients. Better function, more strength, faster healing, less pain, fewer heart attacks, longer life, or measurable improvement in quality of life. That distinction matters a lot for CJC1295 because it's appeal rests on stimulating the growth hormone pathway. And we already have a much more direct way to interrogate that pathway, giving growth hormone itself. In people who are truly growth hormone deficient, replacement can matter. In a few specific clinical conditions, such as HIV associated light but distrophy, targeting this pathway can have an incredible role. But in growth hormone replete adults, i.e., virtually everybody listening to this podcast, including me, the results have been surprisingly underwhelming. Growth hormone can produce modest changes in body composition and increases in so-called lean body mass. But lean body mass, as defined in these terms, is actually a very blunt metric. A meaningful portion of that increase can actually reflect water retention and other non-contractile tissue rather than functional skeletal muscle. More importantly, when you look at the outcomes people actually care about, strength, physical performance, recovery, functional capacity, and quality of life, the benefits are generally much smaller than most people imagine and are often absent all together. So that might actually be the strongest argument against using something like CJC1295. We already know what happens when we push this pathway more directly. If directly administering growth hormone has largely failed to produce meaningful functional benefits in growth hormone replete adults, the burden of proof is high for claiming that an indirect growth hormone releasing hormone will produce dramatically different results. So the issue is not whether CJC1295 is biologically active. It is. The issue is whether that activity translates into a meaningful human benefit. That dose we understand with risks worth accepting. For CJC1295, I think that case has yet to be made. And Peter, I think given what we talked about, one of the common follow-up questions, and we see it a lot is going to be the amount of people who will write or ask us who insist they've been on one of these peptides and it's worked, or they have friends who have tried it and it's worked for them. So how do you respond to people who say yes, but what about all these people that these peptides helped? I really do want to handle this question with some empathy because these stories are sincere and I hear them constantly and I'm not just hearing them directly. I'm hearing them indirectly from patients who are sharing stories of their friends or family members. But a testimonial describes what happened after someone took a drug. They can't tell you what would have happened without it. It also fails to often reflect what else was being taken or done with that drug and those counterfactuals are the whole ball game. So start with the biology of injuries. So musculoskeletal injuries tend to improve on their own and they fluctuate a lot. People almost always start a peptide when they're at their worst, which is exactly when you'd expect things to get better anyway, drug or no drug. That's simply regression to the mean. This is a well-documented phenomenon in human physiology. Then layer on everything else people are doing at the same time. They're probably resting, modifying activity, doing physical therapy, perhaps taking anti-inflammatory drugs, sleeping better, eating better, training smarter, and perhaps even taking anabolic agents. BPC157, CJC1295 or some other peptide stack is just one part of a sea of variables and yet it always seems to be the thing that gets the credit. I'll share with you one brief example, a friend of mine who wanted to start peptides said, you know, another friend of his was taking it and it was having a remarkable effect. And he said, "Look, I'm even going to share with you the pre and post photos." So he sent me a photo of his friend before and after he was on his peptide stack. And there is no denying this photo. There was an enormous improvement. And I said, "This looks amazing. There's no denying it. What else was he doing?" He said, "Well, he also started exercising and he was taking Terzepotide and he changed his diet, of course. because of the tersepitide, and I think he was taking testosterone. But it was amazing to me that this otherwise very intelligent person was attributing the benefit to the wolverine stack of peptides that this patient was taking. Okay, now let's talk about the placebo effect, which is genuinely powerful for subjective outcomes like pain and how recovered you feel or how much energy you have. Nobody injected one shoulder with the drug and then the other shoulder with saline in a blinded way. That seems to not happen. That's what needs to happen to answer this question. And then you add reporting bias. The person who got better posts about it. The person who saw nothing quietly moves on. Anacdotes are great. They can generate hypotheses, but they can't tell you the size of an effect. Who benefits the right dose or how rare they are. Never mind what the harms are. And Peter, can we talk a little more about the placebo effect? Just because that's something that's applicable even beyond peptides. And so how much of the proposed effects could or should be attributed to the placebo effect? I mean, some of it could be, but the point requires precision. Many peptides come with a powerful story around them. That's true for something like red a true tide and it's also true for something like BPC157. The difference is that for some peptides, controlled human trials help separate the effect of the molecule from the expectations surrounding it. For others like BPC157, the story is powerful and the human outcome data are thin. Even when a peptide is biologically active, the perceived benefit can still be shaped by expectation, behavioral change, and the ritual of treatment, along with the broader story attached to it. And that matters because peptides are rarely presented neutrally. They are introduced as regenerative molecules and something that succeeds where conventional medicine failed. That's a great story. By the time many people take them, they have already absorbed a powerful narrative about what it is supposed to do. Peptides as a broad category have almost every feature that can amplify that response. Social media testimonials, authority from a clinician or peptide clinic, real cost, subcutaneous injection, which just somehow feels more official and more serious. And the feeling of using something advanced and biologically targeted. That is potentially a very persuasive story. Pain is probably the cleanest example. Placibo response in pain trials can be large because pain is shaped by attention, expectation, threat perception, sleep, mood, and context. If someone believes they are using a powerful analgesic compound, especially if they have to inject it, that perceived effect can be very real. So when I bring up randomized control trials, I am not trying to be an academic gatekeeper. I am trying to understand the answer to the attribution question among other things. You may know someone who claims to have improved taking a peptide. The RCT tells you how much of that improvement belongs to the molecule after you account for the story, ritual, attention, and expectation. We see this even with drugs that clearly work. In the Step 1 study, Semaglutide produced far more weight loss than placebo, so the drug effect was real. But the placebo group, who believed that it was likely they were getting a weight loss drug, still lost weight. That does not mean the placebo was fake, and it was an actual drug. It wasn't. It means trial context, lifestyle support, adherence, expectation, and follow-up can move outcomes. The RCT is there to tell you how much additional benefit belongs to the drug. That's the key distinction. For a peptide with strong randomized human trials, we can say, yes, there is a story around it, and the molecule adds this much measurable benefit beyond that story. So for something like BPC157 and other gray market peptides, the controlled human evidence that separates the molecule from the mythology is curiously absent. When the story is powerful and the evidence is thin, anecdotes become very easy to overinterpret. Controlled human trials are how you separate the drug from the drama that surrounds it. Peter, what is that FDA fitting to all of this? There's a lot of controversy around the FDA and peptides, and so how do you think about FDA approval when thinking about how you would use or not use peptides? Whether you love the FDA or hate the FDA is beside the point, the better question is what information do you gain and what information do you give up when you choose a drug that has completed formal development with the FDA versus one that hasn't? That's it. What completing formal drug development gives you is much more information, and this information allows you to make evidence informed decisions. It tells you that the actual drug has been shown to produce a defined benefit in a defined human population. It gives you a study dose, a formulation, a route of administration, and a pharmacokinetic profile. It gives you a characterized safety profile known contraindications known drug interactions and monitoring requirements. It also gives you manufacturing standards around identity, potency, purity, stability, sterility, and lot to lot consistency. It's a lot of stuff here. With approved drugs, those questions are at least formally addressed. With many non-approved peptides, they are virtually all unanswered. An important point. FDA approval does not automatically mean the drug is safe. Approved drugs can still cause harm. Some are later restricted, reliable, or even pulled from the market. That's part of what a monitored drug system is supposed to do. Again, I can think of countless examples of drugs that get pulled off the market when post-market surveillance either demonstrates the efficacy is not large enough or the side effects or unwanted off-target consequences of the drug are too great. This is a reason that approval is indication specific. A drug may have a reasonable risk benefit profile in one population, but a very poor one and another. One of the very popular peptides SS31 is a good example of this. It may make sense to approve a mitochondrial targeting peptide in people with Barth syndrome, which is a severe life limiting mitochondrial disease based on limited evidence. That does not mean we have enough information to make an informed risk benefit calculation for a healthy person taking it for energy, performance, or longevity. A risk that is acceptable when the alternative is early death may be completely unacceptable when the expected benefit is speculative. What do you lose by sticking with approved drugs? Well, you lose early access. You may lose cheaper options. You lose access to compounds with marginal benefit that would not survive a formal development process. But I think what you gain is much more important. Evidence, dose clarity, safety characterizations, manufacturing control, and post-market surveillance. That is why I would just have a hard time recommending non-approved peptides. Not because FDA approval is infallible in final, but because bypassing that system usually means giving up the information and oversight that you would need to make a defensible risk benefit decision for yourself. Peter, based on what you just said, what if someone says it is an unimproved peptide, but I got it from either a doctor, a compound infarmycy, or a vendor that has third party testing. Does that solve any of the problems you just laid out there? It solves some of the problems, but actually not most of them. A prescription tells you that a licensed clinician facilitated access, but it does not create any of that missing evidence for the molecule. Physician involvement may improve counseling, injection technique, screening, monitoring, which can matter, but it doesn't prove anything about the peptides working or that the promoted dose is valid or that the product has the same properties as the studied version of the pharmaceutical if you're using something that mirrors that. The same is true for compounding pharmacies. A compounded version of a peptide does not automatically mean it has the same safety and efficacy of the studied version. The oversight and sourcing may be better from products purchased online and labeled for research purposes only, and those differences may matter, but the central issue remains. It does not automatically inherit the clinical evidence manufacturing controls or monitoring of a regulated product. Third party testing can help, but it only answers part of the question. HP, LC, or mass spectrometry may be a good example. may confirm the identity, approximate amount, and chemical purity of a sampled vial. And that's very useful information, but it does not say anything about sterility or lot to lot consistency. People are often treating peptides like an over-the-counter dietary supplement. But these can be potent, injectable molecules, and the more a drug can do to the body, the more care I think needs to be given to our thoughts around it. And as a class can be genuinely powerful, which is a reason to be more careful with them, frankly, not less. We can't normalize treating real drugs carelessly. So I would say the answer is a doctor, a compounding pharmacy, or a third-party test may reduce some of the risks of using gray market peptides, but they don't solve the fundamental problems. And what if the gray market peptide is a version of a drug that already has good evidence? So for example, how do you think about gray market GLP1 Agoness? I think one of the biggest misconceptions people have about these so-called research only or gray market peptides is that they assume the molecule is the drug. But it's not. The molecule is only the starting point. This is, I would say, a not obvious point. Take redditruthide as an example. Redditruthide is not just the amino acid sequence. Anyone trying to turn that sequence into a reproducible pharmaceutical has to solve an enormous number of engineering and manufacturing problems that have nothing to do with whether the molecule binds its receptor. Can the molecule be manufactured reproducibly at scale? Can it be purified consistently? Can you demonstrate analytically that every batch contains the same molecule at the same concentration in purity? Now those aren't like bureaucratic details. They are fundamental chemical engineering and manufacturing questions. A pharmaceutical is not simply a molecular structure. It's the successful solution to each of those problems. That's why I think it's a mistake to assume that because two vials claim to contain the same amino acid sequence, they're equivalent. They may not be. Even if the sequence is correct, the manufacturing process may differ in ways that are analytically important and potentially clinically important. When clinical trials show that a drug works, they are not validating an amino acid sequence in the abstract. They are validating a specific product manufactured under specific processes with a specific formulation and specific physiochemical characteristics. The evidence applies to the product that was actually studied, not automatically to every preparation that shares the same amino acid sequence. This is not mainly a regulatory argument. It's an acknowledgement that chemistry, manufacturing, and analytical science are inseparable from pharmacology. If you change the product, you may also change the properties of the drug. And how do you think about the statements that pharmaceutical companies can ignore these peptides because the natural peptides can't be patented? Is there any truth to that? Only partial truth to that. The kernel of truth is that you can't patent a product of nature in its raw form. But patent law leaves enormous room for monetization, and this is the part people miss. Almost none of these peptides exist in nature in the form that's actually used. These routinely patent modified analogues, new sequences, salts, conjugates, delivery systems, manufacturing processes, even specific dosing regimens and uses. Rapamysin met formin in the statins, all began as natural molecules, and were all eminently patentable once modified. Even BPC157 has patents on all its salts and production methods. The pharmaceutical industry is many things, but indifferent to money is not one of them. Lack of pharmaceutical development doesn't prove a peptide doesn't work. But decades of promotion without convincing human efficacy data, despite obvious commercial interest, should lower your confidence that the claimed effects are as dramatic as advertised. We've already seen exactly this dynamic play out. A whole field of companies is racing to develop drugs built on synthetic variations of the same GLP1 peptide biology, a drug based on a peptide found in nature. So if these gray market peptides truly delivered on their claims, that same pharmaceutical industry would be racing to develop them too, and the conspicuous absence of that race should tell you what you need to know. In fact, something a lot of people don't realize is that many of these wellness peptides are drugs that started in the pharmaceutical pipeline, but stopped being pursued for one reason or another. Inadequate efficacy, safety concerns, poor pharmacokinetics, a failure to outperform existing treatments, competition from a better drug or simply the lack of commercially available indication. The cleanest illustration of this is CJC1295 versus Tessamorland. Same underlying biology developed around the same time, CJC1295 reached phase 2 but was abandoned. Tessamorland advanced to phase 3 and received full FDA approval. CJC1295 is actually closer to the native molecule than CJC1295. Its success has nothing to do with being more patentable or more natural. It succeeded because the data were better. So the picture people have where peptides live in some world outside of the pharmaceutical industry has it exactly backwards. These molecules came from inside the industry very often. The CJC1295 is actually named after the pharma company that abandoned it, Conjouquim. The grey market isn't an alternative to pharma. It's the salvage yard for the drugs pharma tested and walked away from. And so Peter as we wrap this episode, and for person who's listened or watched all of this is kind of starting to try and make sense of it, what do you think they should take away about today's peptide landscape? The skepticism I've expressed here is aimed at the grey market wellness ecosystem, not at peptide science. Peptides are a legitimate and powerful class of drugs. As I gave examples of before insulin and GLP ones are the obvious examples of what is possible when you understand the biology, dosing, manufacturing, benefits and risks. The pipeline also supports this. Roughly 100 peptide drugs are already approved. And about 150 more are in clinical trials. And 600 to 700 more are in preclinical development. The area with the most genuine near-term promise or in metabolism, infectious disease, diagnostics and cancer, where a peptide's specificity can be a major advantage. The irony is that the use is most aggressively promotist in the wellness world, brain boosting, recovery and tissue repair are often the areas where peptides face the steepest scientific climb. The blood brain barrier makes central nervous system effects very difficult. Tissue repair is biologically complex and broad claims about healing regeneration or optimization are much harder to validate than claims about a defined disease. So the promise is real, it's just not evenly distributed. Much of what people encounter today in the gray market peptide world falls well short of that promise. Some compounds are biologically unconvincing, some were clinically abandoned, some are investigational drugs being used before development is complete, others are unauthorized versions of real pharmaceuticals, stripped of the manufacturing controls, quality assurance and surveillance that made the original product interpretable. For a generally healthy person, that means the bar should be very high. Higher than it would be for someone with a severe or untreatable disease. If the expected benefit is modest or speculative and the product quality is uncertain, the risk benefit calculation changes pretty quickly. A risk that may be reasonable in a life limiting disease can be unreasonable when the goal is better energy or faster recovery or some vague promise of longevity. And Peter, what would you say to someone who even after listening or watching this is still skeptical around your stance on peptides? Here's the test I'd apply. What observation would prove a given peptide claim wrong? If the answer is none, if every disappointing outcome gets explained away by dose, timing, supplier, stacking, that's not a scientific claim anymore. A hypothesis has to be falsifiable or it can't be corrected by evidence. That standard is exactly what conventional drug development enforces. So efficacy in humans define who benefits characterized dose and pharmacokinetics understand the risks then decide how it should be used. Adoption follows evidence. of the wellness pepper. peptide space has run that order completely backwards. Wide spread use has preceded the evidence on the assumption that evidence will eventually catch up. It hasn't done so for the gray market peptides. If these compounds worked as claimed, the science should be getting more precise over time. Better trials, narrower indications, clearer dosing. Instead, for many of them, the list of claims keeps growing while the foundational questions, the one that would allow you to make truly informed decisions remains open. Yes, the pharmaceutical industry has made its share of egregious mistakes, but those mistakes happen inside a process built to weed out failures. Ninety to 95% of drugs entering clinical trials never reach the market. Run in by a lack of efficacy, safety concerns, poor pharmacokinetics, or weak commercial prospects. You can criticize the industry for plenty of things, but failure is built into the model, and a lot of fails, including some of the most popular gray market peptides. That's the core issue. Not that peptides work or don't work, but that a claim which can't fail isn't a scientific claim, and a field that expands rather than narrows it claims over time is moving in the wrong direction. That's not evidence-informed decision-making. It's marketing, and hope deserves a lot more than marketing. Peter, I think that wraps this conversation, though I doubt it will be our last one we ever do on peptides. So anything else you want to add before we go? You don't share my optimism that this is the last time we have to do a podcast on peptides? I don't think so. I think this will be one that is hit in the future again. Very well. Awesome. Alright, now have a good one. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us a review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. 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