Non-linearity of dosing and pharmacokinetics

[buffoon24]

Most people assume dose-response relationships are linear: take more, get more effect. This assumption drives everything from megadosing to escalating peptide protocols. But what if higher doses actually produce worse outcomes? I have been looking into this topic in depth lately and wanted to share some interesting tidbits. It might get a bit too technical and I apologize in advance for that (you can always ask chatGPT to simplify).

Mental model - The default mental model is straightforward: if 100 mcg of BPC-157 helps, 500 mcg helps more. If 1 mg of a growth hormone secretagogue produces some GH release, 3 mg produces three times as much. This linear thinking pervades peptide communities, leading to dose escalation when results stall and the assumption that aggressive protocols are simply "stronger."

But as you can imagine, the whole reason I am writing this is because non-linear dosing response is what is actually going on. Let me explain what I mean by non-linear dosing. It can manifest through three distinct patterns:

Saturation : Once receptors are fully occupied, additional drug provides zero additional benefit. You’ve maxed out the biological signal.

Diminishing Returns : Each additional dose increment provides progressively smaller benefits—the classic law of diminishing returns where doubling dose might only increase effect by 25%.

Reversal : This one was fascinating for me to find out. Beyond an optimal dose, effects actually decrease or reverse. Higher doses become less effective or even counterproductive.

Growth hormone releasing peptides (GHRP-6, GHRP-2, Ipamorelin) provide the clearest illustration of saturation dynamics:

Saturation dose for GHRP-6 : 100 mcg fully saturates ghrelin receptors on the hypothalamus and anterior pituitary

At 200 mcg : Only ~50% additional effect beyond saturation

At 300 mcg : Only ~25% additional effect beyond 200 mcg

Beyond 300 mcg : Increased side effects (elevated prolactin, cortisol) without proportional GH benefit

This non-linear curve means someone spending 3× as much on a 300 mcg dose is getting perhaps 75% more effect than someone at 100 mcg not 200% more.

Similar examples exist for diminishing returns (GLP-1) and even reversal.

This gets even more interesting and confusing when you incorporate individual demographics and genetics but that's for another day. This is not to scare or prove something here and probably many of you who are cycling know this already. I have been digging more and more into the dose response, half-life etc etc and will keep sharing whatever I find interesting. I believe there is plenty of room to optimize these things and we are likely shooting in the dark right now.

References -

1. Peptides and hormesis. (2003) PMID: 12809429

2. Two Endogenous Antiangiogenic Inhibitors, Endostatin and Angiostatin, Demonstrate Biphasic Curves in their Antitumor Profiles. (2011) PMID: 22013399

3. Therapeutic Efficacy of Endostatin Exhibits a Biphasic Dose-Response Curve. (2005) PMID: 16322254

4. Pharmacokinetic-pharmacodynamic modeling of ipamorelin in human volunteers. (1999) PMID: 10496658

5. Ipamorelin, the first selective growth hormone secretagogue. (1998) PMID: 9849822

6. Rapid Tachyphylaxis of the Glucagon-Like Peptide 1–Induced Deceleration of Gastric Emptying in Humans. (2011)

7. The Safety and Efficacy of Growth Hormone Secretagogues. (2017)

8. Tirzepatide Once Weekly for the Treatment of Obesity. NEJM

9. U-Shaped Dose Response. ScienceDirect Topics

10. Hormesis: U-shaped dose responses and their centrality in toxicology. (2001)

11. Biphasic dose responses in biology, toxicology and medicine. (2013)

12. A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations. (1998)

13. Modeling Biphasic, Non-Sigmoidal Dose-Response Relationships. (2023)

14. Pharmacokinetics and pharmacokinetic–pharmacodynamic correlations of therapeutic peptides. (2013) PMID: 23719681

 

[yrrdead]

Not really related but , are the bullet points just so we know this is AI generated?

 

[Calm Logic]

Mental model - The default mental model is straightforward: if 100 mcg of BPC-157 helps, 500 mcg helps more.

We don't even know definitely if BPC-157 has helped any human being for things like tendon repair. So the dosing is almost secondary.

No one I know hoards BPC-157, even those who swear by it. Maybe I don't know enough people.

 

[DunningKruger]

Dosing aside. There's also the possibility of a black swan event, especially with GH secretagogues. Even at lower doses one can start to have worse reactions, like non-IgE mast-cell activations, Bradykinin-mediated vascular events, or true IgE reactions (anaphylaxis). I hear Mots-C and TB-500 are also capable of evoking such reactions.

Citations:

-Self

-Forum Anecdata

 

[buffoon24]

Not really related but , are the bullet points just so we know this is AI generated?

How do you recommend writing three independent pieces of information related to the same overarching idea?

 

[buffoon24]

We don't even know definitely if BPC-157 has helped any human being for things like tendon repair. So the dosing is almost secondary.

You mean RCT in humans, correct? There are a few non-controlled studies, but not RCT I agree.

 

[buffoon24]

Dosing aside. There's also the possibility of a black swan event, especially with GH secretagogues. Even at lower doses one can start to have worse reactions, like non-IgE mast-cell activations, Bradykinin-mediated vascular events, or true IgE reactions (anaphylaxis). I hear Mots-C and TB-500 are also capable of evoking such reactions.

Citations:

-Self

-Forum Anecdata

Stacking is a total wildcard I agree and there are so many combinations that probably we will never have studies on every possible combination (2^n). I did not know about the Mots-c and TB-500 interaction!

 

[tubby]

I'd be surprised to see reversal when it comes to GLP1-RAs, specifically. When you review the data supplements to the clinical trials, although individual results can be all over the board, the averages trend and the clusters shift towards greater weight loss at higher doses. You'll certain find hyper-responders as well as poor-responders showing up at each dosage level, but that's more about variability between different people. If there were any significant number of people who would actually lose more weight at 2.5mg of a GLP than 5mg then we'd expect that to show up in the averages or as weird skews in the data supplement plots.

 

[woundcarping]

Who here thought there was a linear relationship with dosing and not diminishing returns?

I mean I kinda hope that was a copy/paste, otherwise that’s a lot of work tilting at windmills, it seems.

 

[buffoon24]

I'd be surprised to see reversal when it comes to GLP1-RAs, specifically. When you review the data supplements to the clinical trials, although individual results can be all over the board, the averages trend and the clusters shift towards greater weight loss at higher doses. You'll certain find hyper-responders as well as poor-responders showing up at each dosage level, but that's more about variability between different people. If there were any significant number of people who would actually lose more weight at 2.5mg of a GLP than 5mg then we'd expect that to show up in the averages or as weird skews in the data supplement plots.

As I wrote in the post, GLP-1 falls in the bucket of diminishing returns.

 

[tubby]

As I wrote in the post, GLP-1 falls in the bucket of diminishing returns.

Giving it another read, I see you were listing GLP-1s as an example of diminishing returns, not suggesting that GLP-1s would exhibit reversal. I failed to properly appreciate your highly-precise language the first time through.

 

[tubby]

I suspect the lack of proper reception to your post is the long-list of references you included and post formatting that exhibits the typical tell-tale signs of chatbot output. People are assuming you just copy/pasted the output of a Gemini query. If you actually wrote that yourself, I think you did an excellent job summarizing an unappreciated topic in the peptide world using highly precise language and I'm sorry you're not getting the recognition that you deserve for putting that degree of effort into a post. Although it's quite odd that you'd purposely format your post in a way to mimic the output one would expect to get in response to a chatbot query.

The only reason I'm starting to think you may have written this yourself was the language style in which you responded to my post challenging you, which is the exact style of response I'd expect from someone who understood and had written that OP.

 

[buffoon24]

Coming from an academic background, we use lists and references all the time which I guess sounds like a chatbot

I have been diving deep into topics around dosage, half-life etc. so I am happy to share the knowledge on this forum as it forces me to organize these ideas better in my head.

 

[ftv10hb]

Coming from an academic background, we use lists and references all the time which I guess sounds like a chatbot

I have been diving deep into topics around dosage, half-life etc. so I am happy to share the knowledge on this forum as it forces me to organize these ideas better in my head.

Do you have any thoughts on dosing amounts/protocols/cycles for MOTS-C, Melanotan-2, SS-31, NAD+ or Epitalon? These are ones I’ve been looking into myself with an interest in trying soon, but the research I do and the anecdotes I read have still left me with something of wide variety of possible doses and plans. Anything you’d care to share, even if it’s just supporting or debunking other information out there, I’d be interested to hear.

 

[ftv10hb]

Coming from an academic background, we use lists and references all the time which I guess sounds like a chatbot

I have been diving deep into topics around dosage, half-life etc. so I am happy to share the knowledge on this forum as it forces me to organize these ideas better in my head.

I also am finding mixed information about adding CJC-1295 no DAC to as Tesamorelin/Ipamorelin stack with some saying it would oversaturate or desensitize the receptors while others saying they could complement each other depending on the dosing, or have a benefit to doing Tesa/Ipa in the AM with CJC/Ipa at night. Any thoughts on that debate I’d be interested in as well lol. Thanks in advance for anything you care to share!

 

[tubby]

Coming from an academic background, we use lists and references all the time which I guess sounds like a chatbot

I have been diving deep into topics around dosage, half-life etc. so I am happy to share the knowledge on this forum as it forces me to organize these ideas better in my head.

Thanks for sharing and looking forward to seeing what other topics you tackle here.

I know an idea I've been exploring lately (but haven't pulled the trigger on) is thinking through how a person might try to estimate their own personal half life and ideal dosage levels for these drugs, which might tie into what you're talking about there.

Example: I have a friend with other health problems (including an auto-immune condition) who is on a 5mg weekly dose of brand name Mounjaro. She is a hyper-responder to the point where there will be days where she's simply unable to eat anything at all without throwing it up or becoming extremely uncomfortable. She previously responded the same way to Victoza, although I don't have the specifics there. This made the drugs too effective for her for weight loss (think end-stage cancer patient appearance), but since she didn't know other people taking them she just figured that was normal and didn't question the experience and results. One explanation is "she's a hyper-responder and needs to lower her dose." That's probably correct, but what if her other health problems cause her body not to clear drug from her body as quickly, effectively increasing her half-life from about a week to perhaps multiple weeks? If she sticks with brand-name auto-injectors, she is limited to reducing dosage to 2.5mg and possibly decreasing frequency, but if she was working with a multi-use vial where she could control dosage with more granularity as well as frequency, it becomes an interesting optimization problem. What would be the most efficient protocol to attempt to estimate her actual half-life as well as ideal dosage to balance results against side effects? And might there be folks out there where their mothers perhaps mated with a Gila monster who are experiencing much shorter half-lives where it might make more sense to bump of shot frequency rather than dosage level? It's fun to think about.

 

[buffoon24]

Do you have any thoughts on dosing amounts/protocols/cycles for MOTS-C, Melanotan-2, SS-31, NAD+ or Epitalon? These are ones I’ve been looking into myself with an interest in trying soon, but the research I do and the anecdotes I read have still left me with something of wide variety of possible doses and plans. Anything you’d care to share, even if it’s just supporting or debunking other information out there, I’d be interested to hear.

Do you mean stacking all of them together? I don't know much about them individually beyond academic interest so take my comments below with a grain of salt.

One thing I would suggest to you is to look more into whether NAD+ actually works or not. From what I understand, there's no validated cellular NAD+ transporter. When you infuse NAD+ into your bloodstream, it must be broken down into precursor molecules (nicotinamide, nicotinamide riboside) before cells can use it.

MOTS-C is something I have been exploring recently. FWIW, there is an actual Phase 1b trial with 25mg daily subcutaneous dosing of MOTS-C analog. The primary outcome for that study was NAFLD, and it actually observed improvement in outcomes, but persistent injection site reactions were common.

Epitalon is quite interesting. It seems to have some insane benefits for longevity/telomere length but all the research data comes from one lab from Soviet Russia. However, last year a study was able to successfully replicate the results which gives some hope. The benefits, again, appear to be too good to be true. Perhaps they get blunted in humans, so we won't really know unless more people try out different doses.

 

[buffoon24]

Thanks for sharing and looking forward to seeing what other topics you tackle here.

I know an idea I've been exploring lately (but haven't pulled the trigger on) is thinking through how a person might try to estimate their own personal half life and ideal dosage levels for these drugs, which might tie into what you're talking about there.

Example: I have a friend with other health problems (including an auto-immune condition) who is on a 5mg weekly dose of brand name Mounjaro. She is a hyper-responder to the point where there will be days where she's simply unable to eat anything at all without throwing it up or becoming extremely uncomfortable. She previously responded the same way to Victoza, although I don't have the specifics there. This made the drugs too effective for her for weight loss (think end-stage cancer patient appearance), but since she didn't know other people taking them she just figured that was normal and didn't question the experience and results. One explanation is "she's a hyper-responder and needs to lower her dose." That's probably correct, but what if her other health problems cause her body not to clear drug from her body as quickly, effectively increasing her half-life from about a week to perhaps multiple weeks? If she sticks with brand-name auto-injectors, she is limited to reducing dosage to 2.5mg and possibly decreasing frequency, but if she was working with a multi-use vial where she could control dosage with more granularity as well as frequency, it becomes an interesting optimization problem. What would be the most efficient protocol to attempt to estimate her actual half-life as well as ideal dosage to balance results against side effects? And might there be folks out there where their mothers perhaps mated with a Gila monster who are experiencing much shorter half-lives where it might make more sense to bump of shot frequency rather than dosage level? It's fun to think about.

This is a perfect example to illustrate the personalized dosing argument! I think there are some interesting ideas from the field of pain medication and adaptive dose tapering that can be applied to peptides, too. Given that a critical mass has been crossed for many of these peptides, I believe we should also be able to do some crowdsourced studies to identify if the dose-response characteristic curve can be derived based on demographics or other cheap/easy-to-measure phenotypes. I think the topic of "most efficient protocol to estimate actual half-life" is something that can probably be framed as a computational problem and precisely one of the things that I have been reading up more on and will share soon.

 

[ftv10hb]

Do you mean stacking all of them together? I don't know much about them individually beyond academic interest so take my comments below with a grain of salt.

One thing I would suggest to you is to look more into whether NAD+ actually works or not. From what I understand, there's no validated cellular NAD+ transporter. When you infuse NAD+ into your bloodstream, it must be broken down into precursor molecules (nicotinamide, nicotinamide riboside) before cells can use it.

MOTS-C is something I have been exploring recently. FWIW, there is an actual Phase 1b trial with 25mg daily subcutaneous dosing of MOTS-C analog. The primary outcome for that study was NAFLD, and it actually observed improvement in outcomes, but persistent injection site reactions were common.

Epitalon is quite interesting. It seems to have some insane benefits for longevity/telomere length but all the research data comes from one lab from Soviet Russia. However, last year a study was able to successfully replicate the results which gives some hope. The benefits, again, appear to be too good to be true. Perhaps they get blunted in humans, so we won't really know unless more people try out different doses.

Thank you! I did mean individually, not as a stack, I’m not against stacking them but I want to understand each of them individually as best I can before I get to that point.

That is interesting about the MOTS-C trial, I have seen ranges for dosing from 2mg 3x/wk to 5mg 5x/week; if they are dosing 25mg daily for the study then that alleviates concern I might have had about leaning towards the high end of the range. The ISR seems to be a theme throughout any dosage.

Do you happen to have links to or summaries of the Epitalon studies? If not I will try to find them myself, I’d be interested to know more about their dosing and the results they found.

As far as Melanotan-2 my main question would be whether the fears of kidney damage or serious negative effects are valid or not. Thanks again for your time in sharing your thoughts!

 

[Chili777]

Do you mean stacking all of them together? I don't know much about them individually beyond academic interest so take my comments below with a grain of salt.

One thing I would suggest to you is to look more into whether NAD+ actually works or not. From what I understand, there's no validated cellular NAD+ transporter. When you infuse NAD+ into your bloodstream, it must be broken down into precursor molecules (nicotinamide, nicotinamide riboside) before cells can use it.

MOTS-C is something I have been exploring recently. FWIW, there is an actual Phase 1b trial with 25mg daily subcutaneous dosing of MOTS-C analog. The primary outcome for that study was NAFLD, and it actually observed improvement in outcomes, but persistent injection site reactions were common.

Epitalon is quite interesting. It seems to have some insane benefits for longevity/telomere length but all the research data comes from one lab from Soviet Russia. However, last year a study was able to successfully replicate the results which gives some hope. The benefits, again, appear to be too good to be true. Perhaps they get blunted in humans, so we won't really know unless more people try out different doses.

I'm a big fan of Epitalon after my recent 20-day cycle. I used 1 mg a day intranasally. I started researching it because of my age and TBI history and it's reputed capability to rebuild proper brain signaling and function. There are a few thread on this forum discussing interest in testing it. I think the recent studies you might be referring to are below. I found them very intriguing. These studies moved Epitalon to the top of my list, after starting Reta.

Overview of Epitalon—Highly Bioactive Pineal Tetrapeptide with Promising Properties - PMC

Epitalon, also known as Epithalon or Epithalone, is a tetrapeptide, Ala-Glu-Asp-Gly (AEDG), which was synthesized based on the amino acids composition of Epithalamin, a bovine pineal gland extract, prior to its discovery in pineal gland polypeptide ...

pmc.ncbi.nlm.nih.gov

Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity - PMC

Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between ...

pmc.ncbi.nlm.nih.gov

The Antioxidant Tetrapeptide Epitalon Enhances Delayed Wound Healing in an in Vitro Model of Diabetic Retinopathy - Stem Cell Reviews and Reports

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus and a leading cause of vision loss. Short peptides, such as di-, tri-, and tetrapeptides, have various beneficial activities, including antioxidant, antimicrobial, and anti-inflammatory effects. This study aims to...

link.springer.com