Peptide Injection Reactions: What’s Really Happening & How to Stop It

0:09 Hey everybody, this is Hunter Williams. I hope you are doing amazing wherever you're at in the world. Today's video is going to be about injection site reactions to your peptides and how to fix them. So the TLDR version of this video will be inject peptide that may cause you injection side reactions intramuscularly instead of subcutaneously because that will solve a lot of the problems. But I know you want to know why you may be having and injection site reactions.

0:39 So what I'm going to do today is explain why some people, not all, but some experience these injection sites reactions, there are certain peptides that you probably have more of a proclivity to like the growth hormone peptide. These seem to be the main culprits of injection side reactions but today I want to go over why they happen and more specifically my opinion on why I think some may have them happen more frequently or in a worse manner than others because to be honest, I don't really ever get injection site reactions. Maybe here or there I've had it a handful of times and all the years I'd been doing peptides.

1:14 So I'm going to walk through that and then just explain why and obviously how to mitigate it. And obviously the short answer is inject intramuscularly. You can reduce the reactions dramatically when doing so, but I'm gonna explain why. So I know you guys want to know why, and today's gonna be a longer video of kind of looking at these injection site reactions, what's going on with the body and why they're happening, why you shouldn't be afraid of them, And then what we can do about it. Hopefully you are as excited as I am to film this video today when you listen to it, But thank you, guys, so much. I'll just say before I jump into that, don't forget the link to the PepTide cheat sheet is always down in the description.

1:46 We also have Fully Optimized Health, the best private community on the planet to talk about these items and topics. And without further ado, I'm going to share my screen. And today we're going get into why these injection site reactions happen and how we can fix them. All right. I am Hunter Williams. Today's video is going to be all about injection site reactions, why they happen and how to fix them. And funny little story, I actually looked up cause sometimes I do photos to put on the title screen and I looked at the injection side reaction. That probably won't be the most visually appealing thing to do.

2:17 So I did not put a picture of an injection set reaction, nor did I use a pictures that I have received from countless people in the past who have sent me pictures of their injection type reactions. that they are worried about. Nothing to worry about, but today we are going to go into what's going on here. So a lot of times when we inject a peptide, people are gonna get redness, itching hives, and swelling at the injection area, which is typically in the lower abdomen area where we're injecting subcutaneously. It's a very common side effect of a lotta peptides. The most common culprits seem to be CJC.

2:48 That's usually the biggest one. Ipameralin also happens, Tessamerelin doesn't happen in as many people. but it definitely seems to be worse in the people that it happens to than I will say I've seen with CJC. So anyway, they are usually mild and very short-lived, although a lot of people can freak out. And I want to distinguish this upfront that a of the flushing and increased heart rate people get from CJ C or a CJ see it from Rellen blend, which is usually coming from the CJ. C is not necessarily an injection site reaction. Sometimes it can be, but a lots of times people will get this flushing and that's just common with the peptide itself.

3:22 But, They're obviously bothersome and affect treatment adherence and rare cases. They may herald a more serious allergy if symptoms progress so they can be a little bit more widespread if kept up. So I know a lot of people have these reactions and they will just stop peptides altogether. There'll say peptide are for me. I can't use those peptids or I use the specific growth hormone peptid or whatever it is. It's more common than I probably give credence to in the work that I do.

3:54 But I also think it's more or less a cost of doing business when it relates to peptides. We're going to talk about how we can fix the day, but before we do so, I want to about what's going on there. So we have this immunological mechanism going. Basically what happens is we are creating a local immune activation when we were injecting a peptide. That's very common. It's, very well known. And it doesn't mean anything bad, but we're creating an immune reaction. What happens is when we inject a peptide subcutaneously, the body's immune surveillance cells respond to it because it's a foreign substance.

4:26 Then what happens in response to this foreign substances is something called mass cell activation. Mass cells, which are abundant in the sub-cutaneous and the skin tissue, release histamine and other inflammatory mediators upon activation, which leads to redness, swelling, and itchiness at the site. And then these injection site reactions resemble allergic inflammation without the traditional IgE antibodies. They are often caused by a pseudo-allergic mast cell response.

4:57 We're having this pseudo allergic mast response, which is present in the subcutaneous fat tissue. The activation of the mast cells via the MRGPRX2 causes a local burst of histamine and inflammatory cytokines which produces the pain and that stinging pain that you've probably felt before. The itching and then the wheel and flare skin reaction which is kind of that circular red, nodule-like bumps and everything that's around there. And the pseudo-allergic or non-IGAE hypersensitivity response explains why redness and itch can occur even on first exposure to a peptide.

5:33 that you may have not had allergic reaction to before. Sometimes people don't have this, then it happens later. So a lot of times it's just a hypersensitivity reaction. Now, looking at the mechanisms, what's going on there. So apart from mast cells, there are other immune pathways that over time when using peptides can contribute. We have an adaptive immune response in the body, which basically means that we may develop this response with repeated peptide injections into the same area,

6:04 especially if the peptid or additives are seen as foreign. Like I've talked about before, when we have antibody buildup response or a tolerance response to a peptide, what's going on is the body sees that peptides is a foreign substance. And over time, it is saying, hey, this is foreign substances. I'm going to build up a tolerances to this and basically trigger my immune system to say this isn't going work for me. This is why we either have to up the dose or cycle up peptids. So in some cases, patients can actually form IgE antibodies to a peptide, leading to true allergic reactions instead of the pseudo-allergic reactions that

6:37 are more common at the injection site or even systemically upon subsequent injections. So this might present as immediate hives or anaphylaxis after injection. And then, for example, Tessamrelin's prescribing information notes that about 4% of patients experienced hypersensitivity reactions, including rash, itching, flushing, and redness thought to be allergic in nature. And similarly, there are reports, mostly anecdotal, of individuals developing IgE-mediated reactions to growth hormone-releasing peptides after uneventful

7:08 use for months, suggesting this immune sensitization over time. So again, you may not have it right away, but maybe two months in, all of a sudden you start having this immunoresponse to the peptide. Again, some people have that right way, which is that pseudo allergic response. And then over the time, if it builds up, it can turn into more of the real allergic responses. We also have this immunity mediated phenomenon, where the injection site may show intense redness hives or swelling as part of a broader allergic response to the peptide and re-exposure could trigger systemic symptoms over time, meaning that the symptoms instead of just locally where injection happens could

7:43 go systemic to where you could have hive to other parts of your body. I've seen that before. Another immune mediated phenomenon is delayed type hypersensitivity or immune complex deposition at the injection sites, which has been observed with some peptides. Obviously we can have local inflammation. So injection of peptide can set off local Inflammation through the Injection trauma itself, Which triggers this immune system response. The physiological reaction to the physical injection also causes inflammation, activating complement pathways, tissue mass cells,

8:14 and bringing white blood cells to area. So again, this is going to be one of the reasons we can have this redness, itching, pain is the actual injection trauma. And the normal inflammatory response can be amplified if the peptide itself triggers immune receptors, or if, the person using the peptides immune system has been primed against it. The result is that the whole spectrum of injection site reactions, we could have mild rednes and warmth, due to vasodilation and immune cell recruitment to itching and hives, which is more of the histamine side of things affecting the nerve and the vessels to swelling and induration,

8:45 Which means fluid leakage and cellular infiltration locally. So this is what's going on. Again, I don't want you to be afraid if you've never used peptides before, this Is more or less making something that happens naturally from injecting something sound like a big deal. But to the point, This is What's Going on when people have these types of responses. And again, it's not that everyone has these responses. It's, not again, something that you should really worry about because again this is very common for a lot of approved pharmaceutical drugs that are used regularly.

9:16 So let's look at this idea of histamine. Histamine releases, I think the biggest culprit, again I'm just imprinting my opinion with this. Histamine release is, i think, the greatest culprit behind the itching, redness, and hives at the injection sites, especially the people that have the response response right away on the first injection they have. So as we talked about earlier, mass cell degranulation, whether via the IgE allergy or direct activation, dumps histamine into the local tissue where we injected and the histamines causes blood vessels to dilate and become leaky, which then leads to that red raised wheel around the injection.

9:53 We also have histimines stimulate nerve endings, causes the itching. One telltale sign of Histamine's involvement is the quick onset of itchiness or a hive at the injection site, usually within minutes after injecting. So again, this is not something that's happening long-term. This is kind of that first response right away. And so patients often describe a red itchy bump forming soon after injection, things like CJC and ipamelan. That seems to again be the biggest culprit in the largest sample size that I've dealt with. which is consistent with the histamine allergic response, sometimes called the wheel and flare reaction.

10:23 So we can potentially use antihistamines. There have been users that I have found in my experience, the reporter that taking anti-histamine like Benadryl can temporarily reduce the itching and swelling from these injections, further implicating that histamine is at fault here. I've heard of people taking Benidryll right after injecting and it does seem to mitigate or eliminate the response. That's something you can do. if you're going to continue to inject and don't want to have to experience these problems. However, once the antihistamine wears off, symptoms may return if the peptide is still present in the fat tissue and triggering mast cells.

10:58 So it's not a one size fits all or 100% guaranteed that's going work. Interestingly enough, some peptides structures themselves can actually directly provoke mast So research in immunotoxicology has shown that certain basic peptides combined to the MRGPRX2 receptor on mast cells causing histamine release without the IgE. And then again, to go back to this idea of the pseudo allergic reaction, this is more or less what people are having. And again, this MRG PRX2 receptor on the skin. Mass cells explains why many drugs, including peptides, cause localized pain, itch, and rash without an IgG allergy.

11:32 So again it's just triggering that receptor there that then causes cascaded reactions. And otherwise, peptide are basically tricking mass cells into thinking that there's a threat when really it is nothing. A lot of times the peptid is going to do us very, very beneficial things in the long run. However, in those immediate, within those first few minutes after injection, we're signaling to the skin and the subcutaneous tissue. Oh crap, there's something wrong there. And then it's going to trigger the histamine release and inflammation of the site of injection.

12:03 Again, this is very common in the growth hormone peptide analogs. I didn't find any scientific data to validate this. Well, you can, but basically I think more or less some people have higher percentage of mass cells in their fat tissue than others. And then some people have more inflammation in there fat tissues than other, which then causes this overreaction depending on the nature of their specific fat. Which might not come from lifestyle factors, it just may be that they have a higher genetic predisposition to having more mass cell in the fat When we

12:42 look at the true allergic reactions, which comes through the IgE mediated pathway, this can also occur with peptide injections, although it's much less common. So just to give a spotlight to that, if a patient or a user of a peptides developed Ig antibodies to the peptid or an excipient, subsequent injections could trigger localized hives or even generalized redness and anaphylaxis there. And so for instance, in Tessamerelin, when they looked at clinical trials, a few patients experienced generalized hypersensitivity reactions such as the

13:12 rash and flushing and redness and had to discontinue the therapy because it was so bad. And again, There's people probably out there watching this video right now that have experienced that. And so in practice, someone injects a peptide and gets not only a local reaction, but also symptoms like facial swelling, widespread highs or difficulty breathing. It is more likely that this is the systemic reaction and it needs usually quick medical attention. Now, again, if you get a little bit of a increased heart rate and a lot of redness from injecting your CHC, you don't need to go to the hospital right away.

13:42 but if it is prolonged and it ends up being a problem, yes, you should seek medical attention to which again, these are much more rare, but I did want to throw it out there. So when we look at the local inflammation at injection site, the response can be driven by other mediators alongside histamine. To talk about these mast cells, mast cell release prostaglandins and leukotrienes. Mast cells release these things and then they prolong redness and swelling. And so other immune cells like macrophages and neutrophils may be recruited to the site.

14:15 If the body perceives the injection solution as foreign or irritating, which contributes to these nodules that sometimes people will get where there's a lump there. and that they're staying there for a long time. So basically histamine is usually the primary cause of this immediate itching and redness, whereas immune cell infiltration and cytokines cause any sustained swelling or shortness of the site long-term. And so allergic mechanisms, whether they are IgE or T-cell mediated, can underlie some cases, especially if reactions worsen over time,

14:45 with repeated injections. So doctors usually advise monitoring the injection sites for any escalating reactions to which it would become a problem. And then if simple redness progresses to hives or a sense of swelling, it could indicate a systemic allergic reaction and warrant discontinuing the peptide. But again, just because you have that histamine response right away, when you first inject the peptide does not mean that you to quit the Peptide or does mean anything is bad. Again, is just this initial histamines response because of what is going on there.

15:15 What I wanted to look at too is some variations in why some people can get this and why people some can't. So aside from the peptide itself, the formulation and preparation of the injection can contribute to site reactions. Peptides, as you know, are typically lyophilized powders that must be reconstituted with a dilutin like bacteriostatic water before injection. So improper reconstitution or formulation issues can also lead to irritation. So let's look at these dilutants first. Like I said, we usually use bacteriocytic water to mix the peptides and benzo alcohol is a preservative.

15:50 That's what makes bactericidal waters. It has benzoyl alcohol to keep any bacteria from growing in the peptide over time and keep it stable. However, As in a lot of cases with alcohol, it can sometimes cause local irritation or even allergic reactions. So some people can be hypersensitive to benzyl alcohol. The product information notes that benzo alcohol may cause hyposensitivity reactions in some individuals, even without a true allergy. Benzoalcohol is an alcohol solvent and can cause localized tissue irritation and tenderness. Again, I think in the case of CJJ, more or less, that's the peptide.

16:21 But in lot cases, It can the benzoylalchol in back water that is causing this. And so if you're sensitive, you can use plain sterile water to mix your peptide. to potentially reduce the reaction. However, I would caution you if you're gonna do that to know that the peptide, if your using sterile water, even if we're refrigerating it, you gonna have a higher propensity that bacteria can grow in that water because it doesn't have the benzo alcohol as a preservative. So just be aware that you use steriled water. I personally would only use steril water to mix peptides if I am injecting the whole bottle of a peptid at one time, because then I don't to worry about

16:57 degradation to which it would allow potentially bacteria to grow. And then also in general, the pH and tonicity of the injection solution should be close to physiological levels. So if the peptide solution is very acidic or basic or not isotonic, it can provoke pain and inflammation at the site. And so manufacturers often include buffer salts like mannitol or saline, with peptide vials to ensure a near neutral pH and proper osmolarity when mixed. If a peptid is compounded with proper excipients, the resulting solution might irritate tissue.

17:29 So again, a lot of peptides formulations, especially if you're buying in the research world, come with mannitol. Is it better to have it not in there? Yes, because we have a less likely chance that we're going to have these reactions, but sometimes these buffers or salts can potentially irritate tissue, which then causes a reaction. So again, if it seems to be a common problem, I would recommend you try a peptide that is not made with mannitol.

18:02 But again I've used plenty of peptides with When I'm experimenting on myself and I mordering a new peptide or something like that, I know that there's probably mannitol in it. So it's okay. It's not the end of the world, but in the best, you know, best of all worlds, Now, we can also look at the concentration and volume of how much water is actually used to mix the peptide. So we could have an increased local irritation with concentrated peptides solution. Highly concentrated peptide solutions or large injection volumes can increase local irritations.

18:33 I will give you a brief example with GHKCU. Typically GH KCU comes in a 50 mg or a 100 mg milligram vial. Well, that's obviously a lot more than some other peptides. GHKHC itself is copper, tends to sting when you inject it. However, I have noticed in practice that if I dilute my GHkU with way more bactericidal water, the sting in the reaction is not as bad. Now, why is that? I think because milligram for milligram, we are increasing the amount of milligrams of peptide and keeping the water constant if we're only putting two

19:09 or three mls of water. So milligram for milligram that GHKU is much more concentrated than maybe trisapatite or BPC-157 or TB-500. And so think, again, I'm not going to get into a reconstitution discussion today, but think about how concentrated your peptide is when you mix it and see if that affects the irritation that you may have after. So a concentrated peptides might raise local osmotic pressure or simply present more foreign molecules to immune sensors in one spot.

19:41 Again, we inject GHKCU. If it's a 25 milligram per milliliter solution, that's lot more milligrams of a peptid for one ml in a solution that it is if it's five or 10, which is often the case in most peptides when you're mixing them. So just be aware of that. And some patients find that splitting a dose into two smaller injections at different sites lessens reaction, Which is definitely true in practice. Presumably by reducing the peptide load per site, though this doubles the number of injections, it can potentially kind of split out the bad effects that

20:13 we're going to get from having that histamine reaction. In clinical trials, injection site reactions rates often correlate with the dose. For example, higher doses of a peptide included more frequent or severe site injection. So using the smallest effective volume and allowing the alcohol in the skin to dry before injection can minimize irritation. I always shoot somewhere between 30 units to 60 units that I'm injecting subcutaneously. If it gets over one milliliter, that's a lot of volume to inject into sub-cutaneous tissue into one injection, And so whenever I'm mixing stuff,

20:46 and again, I am not going to discuss case-by-case reconstitution solution issues, but whenever i am reconstituting things, i usually shoot to have somewhere between 30 to 50 or 60 units that i'm injecting per injection. Sometimes i'll have it as low as 10 or 5, But on average, usually i inject around 30 units of a peptide and i mix it accordingly, if that makes sense. Moving on, we can also look at the peptide purity and stability in terms of what is going on here with the reaction.

21:18 So therapeutic grade peptides like Tessamerelin are highly purified, but if you are obtaining them from research, supply or compounding pharmacies, there is the chance. And again, I am not one that bangs this horn a lot, But there's a chance that there could be impurities or endotoxins. There's also the change in pharmaceutical preparations that you could have impureties or in the toxins. purity chain custody and everything that's going on there. But injection site reactions in animal studies have been linked to impurities or aggregates in protein therapeutics that activate immune responses locally.

21:52 And if a peptide vial is reconstituted and then stored improperly, it might degrade or allow bacterial contamination, both of which can cause redness or swelling or even infection at the site of injection. So this would be obviously the warmth, pain, or distinguishing it from just simply the histamine wealth response that we would get. But I will say one, obviously make sure you're refrigerating your peptides. And then also to just make that you are buying them from a reputable source. Again, that's not the topic of conversation today, but it is something that could potentially make your reactions worse depending on where you getting from.

22:29 Now, I would say I think 90 to 95% of research companies are selling good product. They're not selling a thing. Yeah, some may have more fillers than others. but most of the time there's not anybody that is maliciously putting things in there because obviously they wouldn't get repeat buyers and they would have a business. So we can also look at the carriers and delivery systems. Some peptides are formulated in special delivery system that also can cause local reaction. There's a long acting form of Xenotide, which is a weekly GLP-1 peptide that I believe was around before semen glutide, it's actually encapsulated in microspheres.

23:06 So these microsphere sometimes lead to injection site nodules in patients, which look like hard lumps that can persist for weeks. I've heard of this happening with more peptides than just exenatides. They were likely a foreign body reaction to the polymer carrier or a depot of peptide causing prolonged inflammation that turned into that hard nodule. And in the case of exenatide, 70% of patients reported a small injection site lump versus 13% on daily exentatides. chemicals that were in there to extend the half-life to make it a once-weekly injection actually had a higher propensity to have these lumps.

23:41 And few cases progressed as stereo abscesses or granulomas that required intervention, but again, it was just something they noted. Now, CJC 1295 again I think is a major culprit, and especially if you're using CJ C1295 DAC, which stands for drug affinity complex. But basically what that does is it extends the half-life of CJC that you only have to do one or two injections per week. I'm not a fan of it for that reason because typically you have a bad response and I think growth hormone you would prefer to have it act in a pulsatile manner.

24:13 But anyway, some have speculated that the DAC modification of CJC might contribute to the higher incidence of welts compared to shorter-acting analogs like serum rilin or ripper rillin, though it's hard to find real data on this because no one's really tested it. But regardless, any prolonged resistance of a peptide in the tissue, whether it be a slow-release formulation or strong tissue binding, gives more opportunity for the immune system to react and notice it thus increasing the local inflammation risk. So again, the more chance we give the body to have that response, then more likely that we're going to one of these reactions.

24:46 It makes sense. Now, I did want to talk slightly about the reconstitution technique because I think a lot of people don't pay enough attention to this. Even the mechanical process of mixing your peptides can matter. Shaking a peptide bio vigorously, which hopefully you're not doing, can cause the peptide to form micro aggregates or actually denature which might increase the immunogenicity which is basically the likelihood that we're going to have a response to it. So the correct method is to gently swirl or even just let the and sit on the counter.

25:16 And obviously too, when you are injecting the water into your vial, you don't just want to take the syringe and just squeeze the plunger down as fast as you can and shoot the wate in there and have it splash around all in the bottle. You want it to tilt to the side, stick the Syringe down in their and you want slowly allow the Water to come down the Side of the Bottle so it doesn't denature or defragment the Peptide. Additionally, injecting a cold solution straight from the fridge can actually sometimes cause more burning or irritation. So if you pull your peptides right out of the frige, immediately inject right away, sometimes you can have a worse response that could cause irritation

25:53 at the site there. Sometimes, if this is something you struggle with, I don't do this because I usually don t have bad response, but if want to let the peptide sit on the counter for 30 to 60 minutes, again, it's not going to be denatured because it's out of the fridge for 30 to 60 minutes. Anecdotally, some people have said that it reduces irritation up to 99%. So a lot of people, they have a bad response. They'll put their peptide on the counter for 36 minutes, let it get to room temperature, then pull it out into the syringe inject. Lot of times it will come into this syringes easier too.

26:25 and then they typically don't have the bad response or the response is mitigated. So a warm solution likely causes less local vasopasm and perhaps is familiar to the tissue there. And these kinds of practical nuances, which again are hard to find in studies, nonetheless make a noticeable difference in the comfort of peptide injections. Now, like I mentioned in beginning of the video, I think that a lot of this in practice that I've seen, again, hard-to-find this and studies but in practice can be mitigated by injecting your peptide intramuscularly.

26:58 Let's look at why that is. So subcute injections deposit the peptides in the fatty layer under the skin from which it diffuses into capillaries or lymphatics. This route generally produces a slower absorption and longer duration since subcutaneous tissue is less vascular than muscle. On the other hand, IM or intramuscular injections deliver the peptide into muscle tissue which has a richer blood supply, which often leads to a faster absorption and higher peak levels and shorter time. So think sub-Q, slower and longer absorption. IM, quicker and more rapid absorption Now in the context of growth hormone therapy, peptide studies have shown that IM versus sub Q can yield similar overall exposure,

27:37 but sub q tends to flatten the peak and prolong the effect compared to IM, which again, on a case by case basis may be better for what we're looking for. However, When we look at GH-definite children, one trial in GH deficient children found no major differences in IGF-1 response or growth outcomes between sub-Q and IM human growth hormone, but the sub Q route was overwhelming preferred due to less comfort, obviously because the injection isn't as deep. You don't have to use a big of a needle. It's easier to inject sub q than it is intramuscularly pound for pound.

28:09 The key point is that sub-q injections often exit the depot, whereas IM injections allow quicker drug entry into circulation. So for peptides like CJC or Testimonellum that are designed to have sustained action, subq administration is almost always preferred to take advantage of that depo effect. However, if the immune response to the peptide is causing us so much pain and so many irritation, I would rather have it injected intramuscularly and actually be able to get some benefits, relatively all the benefits as we saw in that GH deficient study in children.

28:39 and be able to not have any sort of irritation or issues. So the skin and subcutaneous tissue is more immunologically active environment compared to the muscle, which makes sense, right? That is our outer layer of protection to basically soldiers to something that may cause us harm because the muscle isn't as protected. So that's why the body's strongest fortifications are what protect us from the outside world. It's our skin, and then under the skin is the subcutaneous tissue.

29:09 The skin contains many mast cells, antigen presenting cells and others as a first line of immune defense. Mast cells with the MRG PRX2 receptor are highly expressed in skin but not as prominent in the deeper tissues like muscle. So, therefore, subcutaneous injections expose the peptide to a milieu of immune cells that might react, for instance, releasing histamine, whereas an IM injection places the peptide deeper where there's fewer reactive mast cells. They are likely to cause us to have this immune slash histamines response.

29:39 So practically, this can mean that some individuals experience less visible skin reaction with IM injections. In my case, when I've recommended that, almost 90% of the people come back and say, oh, wow, I didn't have the same bad response that I have to the subq injection. There is plenty of anecdotal evidence showing that switching to IM injection of peptides can reduce the incidence of superficial redness or itch for those who had major issues with subcutaneous injections. And what we're doing is we are bypassing the mast cell population that is more heavily present in the skin.

30:09 Because of it being more concentrated, we're potentially avoiding the MRG PRX2 mediated histamine dump that causes these welts. And then because IM injections are absorbed faster, the peptide spends less time in one spot to incite a prolonged immune response in that skin tissue because it's being faster absorbed into the muscle. There's limited formal research comparing injection site reactions between sub-Q and IM routes for these specific peptides. However, we can look at some other therapies. So let's look epinephrine, which is for allergy is known to work best IM intramuscularly into the thigh because the intra-muscular injection avoids the

30:46 variability of subcutaneous absorption and leads to faster drug levels. Interestingly, epinephrine also causes less local irritation intramuscularly than subcutaneously, likely due to the quick update. So that's one drug that shows that if you are injecting it, you're less likely to have an immune response. In contrast, certain inferior interferion or vaccine formulations given sub-cutaniously cause more local reactogenicity than when given intrimuscally. In the context of growth hormone releasing peptides, some doctors might consider an IM route if a patient has persistent sub-q reactions,

31:20 which I've seen, although this would be off label for drugs like testosterone because on the label it is recommended to take subcutaneously. And obviously too, it can definitely be more painful. Typically you're injecting with a 25 up to like a 28 gauge, depending on how lean you are needle. This is obviously going to be painful, usually it's longer. So you might have a little bit of bruising after, but it it worth it if you not getting this terrible red bump reaction. Like we talked about too, using IM instead of SubQ might change the drug's efficacy profile slightly because of altering the pharmacokinetics.

31:55 So for peptides to rely on steady release, IM can lead to higher peaks but shorter action. It is going to be a trade-off and again, I can't get into a discussion on every peptide, but you might or might not want that depending on what the peptid is. The core immunogenicity does not seem to differ markedly between Subq and IM in studies of protein drugs. Patients on long-term growth hormone had similar antibody rates whether injection was sub-Q or IEM. And this suggests that systemic immune recognition of the peptide like antibody production is more dependent on the peptide's properties in the route.

32:26 So over time, when we look at the administration over-time, it really doesn't make a difference. Really, we're looking at that short- term window when you're having this histamine response that's causing the irritation. Now, in summary, sub-Q injections are generally preferred for these peptides due to convenience and sustained absorption and compliance because obviously pound-for-pound subq injections, let's be honest, are way easier. But they do expose the drug to an immune-rich environment in the skin, and IM injections can reduce the contact with the scan and subcutaneous mast cells and it can increase the absorption rate, which potentially lessens the likelihood of a visible skin reaction, meaning the peptide gets in and gets out quicker.

33:02 So as of now, most efficacy data on CJC, IPA, and Tessa are based on sub QNH use. With sub-Q injection-type reactions being an accepted side effect in a minority of patients, I like to say a cost of doing business of using peptides, there's always going to be a risk profile and the trade-off that we have to make when we want to enhance our life through some of these therapies. I also did want to look at the context of other therapies and examine how common this is. So let's look insulin. Insulin was one of the earliest therapeutic peptides.

33:34 It was historically used and caused injection site issues, especially with older impure preparations. Patients sometimes experience localized allergic reactions or even lipo atrophy, which just basically means the death of the fat tissue in the subcutaneous layer, what you think is good, right? Death of fat issue sounds good. But if we're talking about the subtaneous tissue, that's not the fact we want to kill, we wanna kill the visceral fat. So this is localized loss of fatty injection sites thought to be immune mediated, Which is where we were having an immune response.

34:04 However, modern human insulin analogs are much purer, so true allergic reactions are very rare in less than 1% of patients. But we can still get mild site irritation or fat tissue changes if injection sites aren't rotated. So that's why when people inject insulin, they recommend that you rotate. constantly the injection site. You're not injecting the exact same area every time. So rotating sites helps eliminate lipo atrophy and GH therapy as well. And the same principles apply to any peptide repeated injection in the exactly same spot can chronically traumatize the tissue or incite low grade immune reactions.

34:35 This is why, for instance, with my growth hormone, I always am changing the side and the area that I'm injectings so that not doing too much into one place and do and realize too, if you do do that, it can build up. I've done that just cause not paying attention or whatever. inject the same spot five times in a row, you start to kind of notice, Hey, like it feels a little weird. There's maybe a buildup there. And so that's why it's smart to rotate through. Let's talk about the GLP ones for a second, because they're just one of the more well-studied ones of peptides that we have. So all GLp1 agus are given subcutaneously.

35:08 And there's been more than 1% that have reported injection site reactions. So with daily exenatide, again, we talked about that, the injection side reactions were minor, but the weekly exentatides led to small nodules in around 17% of patients. And some of these nodule were hard and persisted long-term with post-marketing reports of unresolved injection-site masses and even granulomas. And then also high tier anti-Xenotide antibodies were associated with more frequent injections at reactions, suggesting an immune mechanism that was building

35:38 over time. Now, semaglutide and lyrical glutide have less lower rates of such nodules, but a small fraction of patients still get redness or itching from both of those. And the GLP ones kind of show us that even peptides highly homogenous to human proteins, for instance, semaglutide is 94, 94% similar to actual human GLB one hormone. They still can cause local reactions, especially a formulated ways that keep them at the site for extended periods in a depot formulation. We can also look at, I thought this was pretty interesting.

36:08 I want to put it in there. Copaxone, if I'm pronouncing that right, is a mixture of small peptides used for multiple sclerosis given by subcutaneous injection daily. So I think the name of it is also Galatyromer and is notorious for causing injection site reactions in large number of patients, usually pain, redness, and lumps are very common. And MS patients starting this drug, Copaxone, noted that these local reactions, while not dangerous, can be bothersome enough to affect adherence, particularly early on in the therapy.

36:40 So what's happening here is the mechanism involves immune modulation and it likely activates local mast cells and T cells upon injection. And interestingly enough, the use of antihistamines at randomized trial tested Zyrtec to reduce the injection reactions to the drug. It found a slight decrease in immediate post injection reaction scores with antahistamine, but the difference was not statistically significant compared to placebo. And so both groups saw reduction. over time, but prophylactic antihistamine did not dramatically prevent the local reactions.

37:13 So while histamine is involved, there could be other inflammatory pathways that antahistamines alone do not block. And that's why I said earlier, it's not a guarantee if you take Benetrile before and after that you're not going to have a reaction. Now we can also look at monoclonal antibodies and other biologics. Many biologic drugs like monoklonol antibodies are given sub Q and they can cause injection site reactions in 10 to 20% of patients. And they're basically protein drugs, but the principle is similar to the injection prompts these local immune responses.

37:44 And then patients on interferon beta for MS often get red injection sites and some even develop skin necrosis in severe cases. With monoclonal antibodies, injection site pain and redness are among common side effects and they are usually mild. and very common. Interestingly enough, if the same drugs are given intravenously instead of sub-Q, they don't cause local skin reactions, but people have gotten systemic infusion reactions in the past when they've done them IV. And again, the risk of localized immune reaction with the subcutaneous route is there outside of peptides in general.

38:20 It's just something that again is the cost of doing business. So Injection site reactions occur with numerous peptide and protein therapeutic for metabolic hormones to immune modulators and the frequency and severity vary by drug and formulation. transient mild redness is very common and usually harmless. Whereas persistent nodules or severe reactions are relatively uncommon, but documented with certain things and certain therapies. Obviously growth hormone peptides fall in line with other biologics in that a subset of users are just always going to experience local irritation.

38:51 And so as we can recognize this, we recognize what we do about it. So what is a way to mitigate these injection site reactions? One, to rotate sites. So using different injection sites, so for testosterone, patients are instructed to rotation sites around the abdomen, decreasing the frequency of injection side reactions. It avoids the lipo atrophy that we talked about. And then a common scheme is to use opposite sides of the abdomen on alternate days or to cycle through distinct spots weekly,

39:21 depending on what peptide you're using. Obviously, too, we want to us the right injection technique, so ensuring the peptides injected correctly into the subcutaneous layer and not intradermally too shallow. will help with the irritation. So a lot of people are actually not going deep enough. Some people were going too deep. You want to make sure you're getting that 45 degree angle down to get into subcutaneous tissue so that we're not too shallow and ultimately causing more of an immune response than we would have if we weren't going into the subcute tissue. So again, using the right needle length and angle, usually a short insulin needle at 45 to 90 degrees for subcute, depending on the amount of body fat

39:57 you have that will deposit the peptide where it's intended. And again if you had a longer needle, you want to go at more of an angle. If you a shorter needle you can go to a 90 degree angle Injecting slowly can also reduce the tissue distention and trauma from the needle itself. Then after injection one should not rub the site vigorously. Rubbing can irritate the tissues more. Though gently pressing with a drag off for a few seconds is fine if there's minor bleeding. So if bleeding or bruising is an issue, applying a cold back briefly can constrict the vessels. And then some patients find that icing the site for a minute before injection numbs the area and may reduce the initial inflammatory response.

40:32 Others prefer to apply a warm compress. after injection to increase blood flow and dispersion of the drug, which might reduce local accumulation. Kind of like we talked about too, the room temperature solution. So when injecting a peptide solution, that's a room, temperature, this often reduces the stinging and irritation. I'll say for me, more so it does reduce the singing a bit. If I'm inject something that super cold or spend it in a fridge, it's really cold that when I traveled, maybe the fridge was colder than I was used to at my house. Sometimes it doesn't sting way worse.

41:02 The peptide potency also won't be affected by letting it sit in the syringe for 30 to 60 minutes. And like I talked about earlier, even if you want to, you could just draw it into the Syringe out of the vial and let that sit on the counter so that the rest of peptides is still in fridge. You don't have to worry about it denaturing. Again, You're fine if it's 30 or 60 Minutes. you're not going to have worry anything denaturating in that short of a time. But this can help with the post injection pain that a lot of people experience. Again, to avoid problematic dilutants. So if you're having problems with bacteriostatic water, you can maybe switch to saline or sterile water.

41:35 Again just don't use that over a long haul. If you are going to use steril water try to mix it right away and use it, right way and I wouldn't go longer than a couple days of it in sterl water before I would change out. You can also try sterol salene if compatible instead of bacteriotic water and see if the reactions subside. And if using preservative-free dilutin, care must be taken to maintain sterility and use the vial promptly or refrigerate and discard within one to two days, since the lack of the benzoyl alcohol preservatives means a higher risk of contamination.

42:05 There's also topical treatments too, so for mild post-injection redness or itch, applying a topically corticosteroid like 1% hydrosodone can calm the inflammation in the area. You can also apply steroid cream. So this is a trick borrowed from people that have been using insulin in cases of an injection allergy. Doctors sometimes advise a thin layer of a steroidal cream in the site. I don't think you have to go that far, but again, it's something you could do. Also too, like I talked about an oral and histamine like Benadryl taking 30, 60 minutes before the injection can prophylactively blunt the histamines response

42:37 that we get to it. And then you can also use non-sedating histamines. I know for me, Benadryl makes me super sleepy. Some people it makes wired. an hour. So I don't want to do that. That's why I put that on there. We can also reduce the dose or frequency. If feasible, reducing the dos or the frequency can mitigate the reactions. Again, because we talk about the concentration and then the buildup over time.

43:10 Of course, this might not be desirable for the highest efficacy of the peptide, but some regimens allow for flexibility. For instance, some patients take five days on two days off. Where have you heard that before to get days where no injection is given? I think that's good to not have every single day be an injection day. And I adhere to that myself. And then when we monitor it carefully, one might find a balance where the benefits were maintained, but with fewer injections per week, giving the skin more recovery time obviously can help too. So in case of severe recurrent injection site reactions that do not respond to everything we have talked about today, you can I'll consider an alternative route,

43:45 whether that's just not using the peptide altogether, doing something different, using a different peptides. I would say use intramuscularly. That would be my first and go-to line of defense if you have repeated quick reactions to these peptids within a few minutes of injecting them. This could be something that you can try and obviously it's off label, but There is anecdotal evidence. There's not a lot of clinical evidence to suggest that IM is universally better for these reactions. But again, it's going to be more of a case-by-case basis. And again too, I would consider use a different peptide.

44:16 So if you're using the CJC and Impramerelin, throw out the CJC, and just use Imparamerelin. A lot times that solves people with issues. or just use growth hormone itself instead of CJC or Iprimelan. That would be my recommendation to everyone, but I understand there's a use case for growth-hormone peptide. So again, maybe you're using CJT with DAC, go to the no DAC version and see if it happens. Again, this is where everyone's end up in one and it comes in to you having to explain or kind of figure out for yourself and look to yourself to explained like, okay, This is working. This does not work.

44:47 What would be my observation? So monitor the injection sites. So, monitor where you're injecting and if you are having, obviously if have an infection, you should seek medical attention. I would always recommend anyone to that because I've seen people get really bad infections. Definitely need to go see a doctor for that. Fortunately, their sterile inflammatory reactions are far more common than infections when proper technique is used. So if a true allergy is suspected, again, this is going to be more of the long-term response. The peptide should be stopped and you should work with a doctor. And then also too, desensitization protocols exist for critical medications, but for peptides and anti-aging peptids, continuation is usually the safest route.

45:26 More likely than not, there's almost always something that is an alternative that we can use that's not going to cause the same reaction. So, injection site reactions to peptides like CJC, IPPA, and TESLA arise from a bunch of different factors. Usually, it's the local immune reaction via the mast cell histamine release and the peptide's formulation, how it is injected and individual patient sensitivity all play a role. Obviously, there are things that people use outside of peptides that have similar reactions, so we can kind of look to those to serve as an example of

45:57 what's going on. And obviously if you're using the right technique, a lot of this can be mitigated. I will say, if needed, switching the injection route or peptide therapy is considered. Clinical data affirms that these peptides remain effective and generally well tolerated, for instance, test Merlin trials reported injection site reactions on about 25% of the people that use it versus 14% on placebo injections, but they were usually manageable with rotation and did not weigh the benefits of reducing the visceral fat in HIV patients, which is where test merlin was.

46:27 originally given to. So by understanding these immunological and physiological causes of the reactions, clinicians and patients can take steps to minimize discomfort while using it. And again, like I will say, it is a cost of doing business with peptides. If you have to have a little bit of redness that's not overwhelming and not overbearing, I think the benefits outweigh the cost. That is it for the slides. And that to date is the most comprehensive overview of injection site reaction.

46:57 So hopefully that made sense. This is kind of funky one guys, because at the end of the day, everyone's different. Again, like I said, I've maybe had five times in my life to which I have. had injection site reactions and none of them were really that bad. Worst, it was like a mosquito might be for me. Conversely, Taylor has had a few times where she has, I would say pretty bad, but decently bad reactions to where it hurt really bad she had redness for a day or two after. So I know it can be confounding and I it could be problematic for some people.

47:27 At the end of the day, like I said, the TLDR is try intramuscularly. If you're having these reactions and it's not going the way you want and you don't think you can take the peptide anymore, just give an intra muscular a shot. It may mitigate it a lot or it may mitigated completely, but at least you gave it shot and then you could rotate through. And I think It seems like most of the peptides that people have a bad response to, like CJC, there are other options out there like growth hormone, testimonella, that most people can find something that is in their sweet spot and helps out.

47:59 does the job, which is ultimately to help us live optimized rights. So I think for the most part, this isn't as big of an issue, but I do know it happens. And I did know for newbies is something to get really worried about. I will say just to conclude the video, you don't have to worry about this unless you're getting an infection. Definitely consult the doctor if you are getting infection, But in my opinion, This is just kind of a cost doing business. Once you get used to it, once you over the fear of injecting, of, oh no, there's a little bit of redness. Is something bad going to happen?

48:29 You don't need to go to the emergency room or anything like that. You become comfortable with it and you're like, hey, it's cost of doing business. Just like when I go the gym, I'm putting myself at risk of injury, even though I know the benefits from the jam are far worth the risk that I put myself to get an injury. So that's for this one. I would just close out. Thank you guys so much. Let me know your feedback on this. When I noticed one was a bit more long-winded, but I did want to beat, beat it to death or beat the dead horse. But Let me know your feedback on this one. I really, really value and appreciate all the amazing feedback and all of the comments and everything.

49:01 So I appreciate you guys. Thank you so much. but gratitude and love for everyone out there that supports the channel in whatever form, shape or fashion that is. So thank you guys. I hope you have an amazing rest of your day wherever you're at, and I will talk to you in the next one. Peace.