Calm Logic
GLP-1 Specialist
Haha. And, of course, a lot of people never get to (or stay at) the clinical maximum dose.
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I'm not impressed.
- Thread starter BadLouie
- Start date
Haha. And, of course, a lot of people never get to (or stay at) the clinical maximum dose.
Although likely true, that's not necessarily useful.
If you gain back 15 pounds by going off it for a few months, then presumably that first 15 pounds will be easier to lose when you go back on it. Of course, that's more a case of regaining lost ground than it is breaking new ground.
Likewise, if your receptors have developed some degree of resistance due to being on the drug, presumably after being off for a month or two much of that resistance will have subsided. That too will make it stronger when you go back on, but presumably it won't be long before that same level of resistance returns (due to being on the drug again).
It certainly can't hurt to give your body a break from time to time, but it would be surprising if doing so had any sort of multiplier result in terms of achieving greater weight loss VS just staying on it.
trojanpeptide
GLP-1 Enthusiast
Guys, I agree to follow the clinical data; I have a strong background in STEM, I am a trained scientist. I am not the one that claimed what I wrote, it's only something I've read. I understand this is anecdotal, but also, I agree that we may have idiosyncratic reactions to peptides. For example, some are super responders (like me), and some are not.
But either way, I did indeed need to increase amounts during my treatment, as it seemed my weight loss stalled. Whether or not we call this tolerance or 'getting used to being less fed' (metabolic slowdown?), it is my personal experience that I required tapering, so I am not dismissing any evidence whatsoever, no matter what white papers tell me.
But either way, I did indeed need to increase amounts during my treatment, as it seemed my weight loss stalled. Whether or not we call this tolerance or 'getting used to being less fed' (metabolic slowdown?), it is my personal experience that I required tapering, so I am not dismissing any evidence whatsoever, no matter what white papers tell me.
This isn't about us dogmatically asserting that the trial data is the one true light and way that can't be questioned and must be true. I love when people find interesting angles to question that sort of thing. It's more that the experience you just described (experiencing a weight loss stall and then breaking that stall by increasing dosage) is exactly how GLP drugs are expected to work. What would require an unique or novel explanation would be if for some reason that didn't apply to you and you kept losing more weight in perpetuity without reaching a stall.
trojanpeptide
GLP-1 Enthusiast
Here is an interesting excerpt:
"Despite the knowledge from clinical studies posted by this expert user, some form of drug ‘tolerance’ per lay understandings did seem to exist for GLPs, as those who did not gradually titrate their dose, or who returned to the same dose after a period off using, would experience notable negative side-effects:
‘I jumped back in on my old dose which was too high, I spewed up in the night and next morning.’
While a scientific understanding of how GLPs work was important, posters also needed to be aware of the impact of reduced ‘tolerance’ to these drugs from a lay perspective, and consequently even among those who conceptualised decreasing efficacy in line with the thermostat analogy, new or returning users were still cautioned to ‘start low, go slow’".
Off-label GLP-1 weight-loss medicine use among online bodybuilders: Folk pharmacology, risk and harm reduction (linked)
It's open access, interesting read.
Also in that paper are suggestions about cycling between GLPs; bodybuilder stuff, but still, this could be applicable to OP's query.
"Despite the knowledge from clinical studies posted by this expert user, some form of drug ‘tolerance’ per lay understandings did seem to exist for GLPs, as those who did not gradually titrate their dose, or who returned to the same dose after a period off using, would experience notable negative side-effects:
‘I jumped back in on my old dose which was too high, I spewed up in the night and next morning.’
While a scientific understanding of how GLPs work was important, posters also needed to be aware of the impact of reduced ‘tolerance’ to these drugs from a lay perspective, and consequently even among those who conceptualised decreasing efficacy in line with the thermostat analogy, new or returning users were still cautioned to ‘start low, go slow’".
Off-label GLP-1 weight-loss medicine use among online bodybuilders: Folk pharmacology, risk and harm reduction (linked)
It's open access, interesting read.
Also in that paper are suggestions about cycling between GLPs; bodybuilder stuff, but still, this could be applicable to OP's query.
It's definitely worth trying different things and seeing what works for you. Agreed on that!
I think some confusion here might stem from "tolerance," which you've mentioned a few times. In biological systems it's very common for them to possess defense mechanisms where the response rate to a given stimulus is reduced as the stimulus increases and that's usually described as a lack of tolerance. The quote you shared is in regards to side effects to a medication at a given level being greater after someone stops taking that medication for a while. That's a very well established phenomena in general.
I think you might be trying to apply the same logic to weight loss by looking at GLPs as the input, weight loss as the output, and labeling a weight loss stall as a loss of tolerance. I can understand the temptation to look at it that way, but doing so is going to lead you to reaching faulty conclusions. There are a whole lot of other steps and pieces that fall into place between putting a needle in your body and the eventual weight loss that follows. It would be like trying to relate pushing harder on the gas pedal of your car to the number on your speedometer going up. Although superficially you might experience something resembling a lack of tolerance at higher speeds (you can only speed up so much), that's probably not a useful way to thinking about it since it's going to neglect if you're driving up or down hill, how many people are in your car, and all sorts of other factors that are also important.
It's the receptors in your brain (and other parts of your body) that develop a reduced tolerance to GLP1 signaling. That reduced tolerance likely reaches an equilibrium well before a weight loss stall is realized. If a 1mg weekly dose would ultimately lead to a 20 pound loss (in your particular body undergoing your particular lifestyle), it might take months for that stall to be observed, but the reduction of tolerance to GLP1 signaling likely happened within weeks of you starting the medication at that particular dosage.
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Super Trips
GLP-1 Enthusiast
Welcome to the high dose club my friend! I am also a person that has responded well at high doses but never at the lower doses. I have maxed out just about every GLP 1 and every other type of peptide you can imagine. It's frustrating when people here don't understand what I'm going through and Just think it's all about hype or just wanting to get clicks and views but it is actually a problem that I've been running into and had to up my doses so high after taking breaks and trying every type of different scenarios. My Max has been 60 MG of Tirzepatide and well over 8 MG of cagri in a week. I also have stacked sema and a handful of other combos including survo ,reta and just about everything you can imagine.
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Calm Logic
GLP-1 Specialist
Have you tried a continuous glucose monitor, such as to see how much improvement on 30 mg of tirz vs. 15 mg?
Good-Heart6425
GLP-1 Enthusiast
I’m having recent memory loss recently as well, which is new despite my geriatric status. It seems that when I consume more protein, memory function returns, or at least, improves.
Frankbooth
GLP-1 Apprentice
Time for 20mg/week reta
trojanpeptide
GLP-1 Enthusiast
Are you stacking NMN (or NR or NMNH)? If not, consider adding this.
edit: also you may want to check this paper out.
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randompersonrandom
GLP-1 Specialist
I think it's almost time to lay off the Survo. I mean, I know it is, because I said I would when I got to goal. But I think my dose is too high. I don't want ANY protein in the last week or two. I just want rice bowls with a bite or two of tofu, low carb wraps with salted cucumber and a thin slice of avocado, bowls of ramen with cilantro and green onions, and that's it.
Good-Heart6425
GLP-1 Enthusiast
Caution, avoid sarcopenia. It’s easier to avoid than it is to reverse muscle wasting and all the comorbidities sequelae.
lessthanhalf
GLP-1 Specialist
Without knowing what your start weight was and what your current weight is, it is impossible to say anything about how well the medication is or is not working.
If it works in you exactly as well as the average person in the studies, then if your current weight is 20% less than your start weight it has done exactly as advertised.
But it will seem like it is no longer working.
You will no longer be losing weight and you will be more hungry than you were at the start on that dose, because losing weight makes you more hungry, as your body tries to defend a unhelpful set weight in your brain. But if you keep taking it and are not gaining weight then it is working perfectly.
There is no evidence of tolerance to the appetite suppressing effect of these drugs or their effect on weight loss over time.
Antibodies to them are actually very common but unlike most other biological therapies, the antibodies very rarely neutralise the drug, so really have no effect.
Unfortunately half of the people taking a given medication like tirzepatide will lose less than the average amount of weight, and the reality is these medications are not even close to being good enough to fix obesity for most people with a BMI over 35. But even losing 10% is better than nothing and does reduce long term health risks. Before GLP's any diet or medication that got close to 10% effectiveness was considered a major success. But in general unless you have permanently changed your eating and exercise patterns, weight will return to previous weights if you stop the GLP.
The drug companies are very actively investigating add on drugs for GLP's, such as cagrilintide and many others much further away from success, to improve maximum weight loss and reduce muscle loss.
Adding in extra treatments in this situation is an option, but how safe it is, is not really proven yet, and if older and generally less healthy it would carry extra risks. Adding in extra medications when on less than the standard maximum dose makes little sense to me. And whether those risks are worth taking is your decision , but are harder to justify for less severe obesity. As you have already tried semaglutide that is not much use, and I am assuming you did not get a lot of side effects from tirzepatide, the the options are adding low doses of retatrutide or cagrilintide. For safety reasons if using them as add ons starting low and increasing doses very slowly is a good idea. The other option is higher than 15mg of tirzepatide.
To maintain my weight loss of 54% I have had to use tirzepatide 15mg plus 5mg retatrutide, plus total avoidance of all high calorific density or high fat/sugar/carb foods for 3 years, treating those foods as an addiction problem I need to avoid, basically only eating very lean meat, no fat, fruit and vegetables.
Losing lots of weight long term is extremely difficult, before GLP's success rates were about 5% without surgery. Unfortunately if you respond less well than average to GLP medications there are no good approved solutions yet, just some experimental options, but they are working on it , and on a very large scale - there are about 200 new anti obesity drugs currently in development.
If it works in you exactly as well as the average person in the studies, then if your current weight is 20% less than your start weight it has done exactly as advertised.
But it will seem like it is no longer working.
You will no longer be losing weight and you will be more hungry than you were at the start on that dose, because losing weight makes you more hungry, as your body tries to defend a unhelpful set weight in your brain. But if you keep taking it and are not gaining weight then it is working perfectly.
There is no evidence of tolerance to the appetite suppressing effect of these drugs or their effect on weight loss over time.
Antibodies to them are actually very common but unlike most other biological therapies, the antibodies very rarely neutralise the drug, so really have no effect.
Unfortunately half of the people taking a given medication like tirzepatide will lose less than the average amount of weight, and the reality is these medications are not even close to being good enough to fix obesity for most people with a BMI over 35. But even losing 10% is better than nothing and does reduce long term health risks. Before GLP's any diet or medication that got close to 10% effectiveness was considered a major success. But in general unless you have permanently changed your eating and exercise patterns, weight will return to previous weights if you stop the GLP.
The drug companies are very actively investigating add on drugs for GLP's, such as cagrilintide and many others much further away from success, to improve maximum weight loss and reduce muscle loss.
Adding in extra treatments in this situation is an option, but how safe it is, is not really proven yet, and if older and generally less healthy it would carry extra risks. Adding in extra medications when on less than the standard maximum dose makes little sense to me. And whether those risks are worth taking is your decision , but are harder to justify for less severe obesity. As you have already tried semaglutide that is not much use, and I am assuming you did not get a lot of side effects from tirzepatide, the the options are adding low doses of retatrutide or cagrilintide. For safety reasons if using them as add ons starting low and increasing doses very slowly is a good idea. The other option is higher than 15mg of tirzepatide.
To maintain my weight loss of 54% I have had to use tirzepatide 15mg plus 5mg retatrutide, plus total avoidance of all high calorific density or high fat/sugar/carb foods for 3 years, treating those foods as an addiction problem I need to avoid, basically only eating very lean meat, no fat, fruit and vegetables.
Losing lots of weight long term is extremely difficult, before GLP's success rates were about 5% without surgery. Unfortunately if you respond less well than average to GLP medications there are no good approved solutions yet, just some experimental options, but they are working on it , and on a very large scale - there are about 200 new anti obesity drugs currently in development.
I gained some during the holidays on max dose Tirz, 1.5 years in. Stacking Survo for a couple of months, still not seeing results. Three days ago started tracking calories again, prioritizing protein, avoiding sugar, increasing water, and fasting until noon. Your basic bitch diet plan. Instantly feel like my meds are working for me again. So this is just one persons experience, but I think what you eat can help support (or not) the effects of the meds. I'm actually really hopeful about this development. I'm down to just Maz and Cagri to try next (once I've gone up as far as I feel good about on the Survo stack) and was starting to despair.
I'll also say that all the Tirz studies show diminishing returns past 10mg increases, and that was my experience as well. So I'm reluctant to rely on going up past 15mg as a potential solution. The difference in 'feels' for me from 10 to 12.5 to 15 was not much.
I'll also say that all the Tirz studies show diminishing returns past 10mg increases, and that was my experience as well. So I'm reluctant to rely on going up past 15mg as a potential solution. The difference in 'feels' for me from 10 to 12.5 to 15 was not much.
Nipponpeptide
GLP-1 Novice
🚫No Source Discussion🚫
You’re definitely not alone in this, even though it feels that way when everyone around you is melting weight on half-doses.
A few thoughts from seeing a lot of these cases play out:
First — yes, GLP tolerance is very real, especially in people who’ve been on GLP/GIP meds continuously for a long time. Two years on tirz at escalating doses puts you squarely in the “high exposure / receptor-adapted” bucket. What you’re describing (strong early response → diminishing returns → short-lived benefit after breaks) is unfortunately pretty common.
Second — Cagri hype vs reality: Cagrilintide can be excellent for food noise, but it’s not magic, and it doesn’t hit everyone the same. In people already maxed out on tirz, it often shows a narrow therapeutic window: you get a few days of benefit when you cross a threshold (like your week-3 experience), then the CNS adapts fast. What you described at 1 mg helping briefly, then doing nothing, fits that pattern exactly.
Third — the RETA “nothing burger” story isn’t rare either. Reta shines most in GLP-naïve or moderately exposed users. In heavily adapted users, the glucagon activity often doesn’t translate into appetite suppression — sometimes it even offsets it. So I wouldn’t take your RETA experience as proof that you’re broken.
A few practical points / “non-cheat-code cheat codes” people overlook:
• More drug ≠ more signal once central appetite pathways adapt
• Mixing multiple GLPs at high dose often accelerates tolerance rather than fixes it
• Psychological food noise can persist even when peripheral appetite is suppressed — especially after long-term IF/keto
• Chronic OMAD + GLPs can increase rebound hunger signaling over time
On the >20 mg tirz idea: yes, people do it, and yes, some report benefit — but for many it’s short-lived and just pushes the tolerance ceiling higher. It can work, but it’s rarely a durable fix unless something else changes.
What might be unique with you (and people like you):
• Long-term GLP exposure
• Strong hunger signaling baseline
• CNS adaptation rather than gut resistance
• Possibly elevated ghrelin/cortisol response from prolonged fasting history
If I were troubleshooting (not medical advice, just pattern recognition):
• Consider a true GLP washout longer than 90 days or
• Temporarily simplifying instead of stacking (single agent, strategic dosing)
• Re-thinking fasting structure while on GLPs (sometimes less fasting = less noise)
• Targeting non-GLP appetite drivers instead of pushing doses endlessly
You’re not crazy, broken, or alone — you’re just further down the adaptation curve than most people posting success stories. Appreciate you laying it all out in detail; threads like this are way more useful than “lost 20 lbs in 6 weeks!!” posts.
Curious to see how 1.5 mg Cagri treats you, but I’d manage expectations and watch duration of effect more than intensity.
I may need to try reverse dieting. I've been plateaued for over a year. and I can eat more or eat less and still the scale doesn't change.
You actually can't continuously eat more or less. Yes, your body adjusts your calories out but it can't do it infinitely.
Retazempic
GLP-1 Enthusiast
I lowered my dose for a while so I could eat more for awhile and it helped me
I was terrified of dropping my dose, but in my case it helped
After awhile, I went back to the higher dose
I don’t remember how long I did it at the lower dose, but it was probably 2 or 3 weeks
TooBigtoFail
GLP-1 Enthusiast
Cagri still works for me. Started Tirz 84 weeks ago. Six months into it, was at ~12.5mg. Added Cagri and titrated up very slowly. Months later, added Reta low dosage and bumped Tirz to ~20mg/w (actually 2x10mg/week). After 6 mths on Cagri (was at 0.9mg/w), had to stop it, was too nauseous with triple stack. Bumped up reta slowly, and decreased tirz to 0 in about 3 months. Restarted cagri 0.8mg/w about a month ago, with Reta now at 8mg/w. Down a few more ## in past few weeks. Lost 91# so far in 84w. Throughout the past 12 months, been cycling TA1/Epi/glow/MOTS/SLU. No exercise. The past few months been only loosing about 1# a week. I eat 50% less food that I used to. I do protein shake for morning. If I skip, I get the munchies at night. Daily is protein and fibers only. Took me over 12-14 months to get hunger control and food discipline. I learned to love/hate Cagri. It makes me want to puke each time I see/smell food, but it works. I have enough Tirz/cag/reta for 3 years. If taking glp1 is a life sentence, I am ready. I need another 15 lbs to hit the healthy, non overweight, BMI. Went from size XXL 44, now Smal/med 33 waist. All vitals are normal but my A1C low @4.7 (glp1 cocktail). It does take a few weeks for glp changes to take full effects. I always titrated up/down slowly. No sudden stop. I have a daily log to track progress and dosage. I would say don't give up, be patient, and try different stacks if you must.
I had plastic surgery and I was off it for 6 weeks with zero dieting and started back and I'm still stuck.
Olbartmore77
GLP-1 Novice
🚫No Source Discussion🚫
Can anyone recommend a Reta starting dose coming from 15mg zepbound?
Retazempic
GLP-1 Enthusiast
I would think they are just too different to do that
CNCCurrency
GLP-1 Specialist
How are they that that different? GLP1 and gip in both?
Olbartmore77
GLP-1 Novice
🚫No Source Discussion🚫
Really? How so?
Super Trips
GLP-1 Enthusiast
i'd say 3-5mg but reta does differ from tirz though
CNCCurrency
GLP-1 Specialist
add the glucagon, don't see that making that much difference
Olbartmore77
GLP-1 Novice
🚫No Source Discussion🚫
In the sense it’s a triple agonist?
Retazempic
GLP-1 Enthusiast
It’s not simply Tirzepatide + glucagon
The amount/ratio of GLP1 and GIP in Tirzepatide is VERY different from the amount/ratio of those peptides in Reta
CNCCurrency
GLP-1 Specialist
Not what I said, but Your proof to that would be?
