Non-linearity of dosing and pharmacokinetics

[LazysodLondon]

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

Not sure if I missed it and apologies if so but this list of references would be easier to reference if linked to the point they are making. As is, it seems more a recommended reading list. Not that thats a bad thing and I have saved a few to look at later.

Again, if missed apologies!

 

[Mr. Blonde]

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.

I always keep some bpc 157 and tb 500 on hand just in case.

 

[lessthanhalf]

I found this a while ago as having useful dose response analysis for different GLP's. It has some formulas it worked out relating dose to effect for the different ones over time.

I was and am more interested in maximum effects as I am trying to keep off a 54% weight loss, and I did get chat gpt to try to extrapolate a maximum effect from higher than standard doses from the formulas, as actually doing the math was going to be hard. The standard maximum doses of the common glp's sema, tiz and reta are all not that far from the diminishing returns area, where you only get a bit of extra weight loss from much higher doses and a lot more side effects. The high dose semaglutide trials showed this quite clearly. There did seem to be more room at the top of the dose range for retatrutide than the others from memory. Just looking at the difference in weight lost between the two highest doses used in the trials on the graphs gives you a useful indication of how close the maximum standard dose is to the maximum weight loss dose.

this is the study

Obesity Pillars 13 (2025) 100162

Available online 30 January 2025

Comparative efficacy and safety of GLP-1 receptor agonists for weight

reduction: A model-based meta-analysis of placebo-controlled trials

In response to Tubby's comment above talking about a friend who is using brand name tirzepatide - you can get intermediate doses between 2.5 and 5 mg in the legit pens by counting the clicks, there are tables online of clicks per dose.

 

[lessthanhalf]

Also if you have a link to the above mentioned phase 1 trial of mots c in humans I would like it . I looked a week ago to see if there was anything and did not find it , only a study of a modified version of mots c in humans.

 

[Labcat]

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.

Realistically it would be more likely to have been the father

 

[Labcat]

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!

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 for telling us the exciting news qqqaabout the epithalon study replicating the results! I have not come across that despite my attempts to search. Would you happen to be able to have a link, the text, or a copy of that paper?

This whole subject is quite interesting. I hage always assumed that people titrate slowly to effect, though I assume that diminishing returns is accepted because of i creased returns obtainable in no other eay (easily). And in subtle peps, placebo might obscure true effects of increasing dose…

Do you have some good examples of reversal? Or any peptides you suspect that of?

 

[DunningKruger]

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

OMG, YES! I'm currently taking the bare minimum of Epitalon (.5mg, trying to make my only vial last), and am having the the best sleep on it. For the first time in ages, I look and feel rested, and dreams are recalled with such clarity.

Thank you for the juicy studies to peruse.

 

[fuchufuchu]

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

great post! i appreciate the depth of information you provided as well as the list of sources you used. would you mind sharing where you found that increasing glp-1s dosage fall under the category of diminishing returns? i apologize if this is among the list of sources you have, i haven’t had the time to peruse through all of them yet.

 

[buffoon24]

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!

Yes, here is the epitalon study - https://pubmed.ncbi.nlm.nih.gov/40908429/

For Melanotan-2, I have heard of kidney damage as a side effect, but I believe it occurs at higher doses. I am not much familiar, so you should check things out. Here are two important papers -

1. https://pubmed.ncbi.nlm.nih.gov/23121206/

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7148395/

 

[buffoon24]

Not sure if I missed it and apologies if so but this list of references would be easier to reference if linked to the point they are making. As is, it seems more a recommended reading list. Not that thats a bad thing and I have saved a few to look at later.

Again, if missed apologies!

You make a good point, will keep this in mind in the future

 

[ftv10hb]

Yes, here is the epitalon study - https://pubmed.ncbi.nlm.nih.gov/40908429/

For Melanotan-2, I have heard of kidney damage as a side effect, but I believe it occurs at higher doses. I am not much familiar, so you should check things out. Here are two important papers -

1. https://pubmed.ncbi.nlm.nih.gov/23121206/

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7148395/

Thank you! I will definitely look into them

 

[buffoon24]

Also if you have a link to the above mentioned phase 1 trial of mots c in humans I would like it . I looked a week ago to see if there was anything and did not find it , only a study of a modified version of mots c in humans.

Yes sir, there you go - https://www.globenewswire.com/news-...1-Under-Development-for-NASH-and-Obesity.html

The drug they are talking about (CB4211) is a MOTS-C analog

 

[buffoon24]

Thank you for telling us the exciting news qqqaabout the epithalon study replicating the results! I have not come across that despite my attempts to search. Would you happen to be able to have a link, the text, or a copy of that paper?

This whole subject is quite interesting. I hage always assumed that people titrate slowly to effect, though I assume that diminishing returns is accepted because of i creased returns obtainable in no other eay (easily). And in subtle peps, placebo might obscure true effects of increasing dose…

Do you have some good examples of reversal? Or any peptides you suspect that of?

Epitalon is definitely quite interesting! It is one of those too good to be true kind of peptides BUT almost all the research is from Khavinson's St. Petersburg lab.

 

[buffoon24]

great post! i appreciate the depth of information you provided as well as the list of sources you used. would you mind sharing where you found that increasing glp-1s dosage fall under the category of diminishing returns? i apologize if this is among the list of sources you have, i haven’t had the time to peruse through all of them yet.

These are good papers to look at for the dose response - https://www.nejm.org/doi/full/10.1056/NEJMoa2107519 https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

Note that these studies are not studying dose response as the main thing, but they have looked at how primary outcomes change across 3 different dosing regimen

 

[Chili777]

Yes, here is the epitalon study - https://pubmed.ncbi.nlm.nih.gov/40908429/

For Melanotan-2, I have heard of kidney damage as a side effect, but I believe it occurs at higher doses. I am not much familiar, so you should check things out. Here are two important papers -

1. https://pubmed.ncbi.nlm.nih.gov/23121206/

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7148395/

That was the second one I posted above. I hadn't seen anything more recent. I hope they keep doing proper research on it.

 

[Labcat]

Thank you for telling us the exciting news qqqaabout the epithalon study replicating the results! I have not come across that despite my attempts to search. Would you happen to be able to have a link, the text, or a copy of that paper?

This whole subject is quite interesting. I hage always assumed that people titrate slowly to effect, though I assume that diminishing returns is accepted because of i creased returns obtainable in no other eay (easily). And in subtle peps, placebo might obscure true effects of increasing dose…

Do you have some good examples of reversal? Or any peptides you suspect that o

Epitalon is definitely quite interesting! It is one of those too good to be true kind of peptides BUT almost all the research is from Khavinson's St. Petersburg lab.

Epitalon is definitely quite interesting! It is one of those too good to be true kind of peptides BUT almost all the research is from Khavinson's St. Petersburg lab.

Some of those papers are visible to us. I’m trying to read some of them. But sometimes work done in countries where scientific advancement is by political influence can be more difficult to get an understanding of whether it’s objective. I don’t have specific information about this context, but I know a lot of highly promoted health research coming out of east germany was not as represented.

 

[Chili777]

Some of those papers are visible to us. I’m trying to read some of them. But sometimes work done in countries where scientific advancement is by political influence can be more difficult to get an understanding of whether it’s objective. I don’t have specific information about this context, but I know a lot of highly promoted health research coming out of east germany was not as represented.

The research we both cited was done in the UK. Here is the full article.

 

[Labcat]

The research we both cited was done in the UK. Here is the full article.

Yes, the cell culture telomere elongation study was done in the UK, sorry, my mind had already skittered along to the oft referred to Khavinson studies for longevity

I was more thinking of the Khavinson Epitalon Thymulin 6 year human study where it appeared to decrease mortality factor of 4 in one group treated for 6 years. The question that immediately arises in my mind is whether the individuals who got 6 years of treatment were the ones who survived or were those not lost to followup. This startlingly not uncommon reversal of cause and effect was seen in a few studies testing long covid treatments. They may have done everything copecetic though, it’s just that I’d feel more confident about their science if I could see more than their conclusions.

Peptides of pineal gland and thymus prolong human life - PubMed

The obtained data confirmed the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care for health maintenance and age-related pathology prevention in persons over 60 to prolong their active longevity.

pubmed.ncbi.nlm.nih.gov

 

[HereKittyKitty]

Thank you for everyone's comments. I have been thinking about this for nearly 2 weeks.