Semaglutide tolerance

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ltts

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Hello everyone, first post in this forum :D

I've been on semaglutide for a year now, starting from 0.5mg weekly to 2.5mg weekly after month 6 until now. I've noticed that the appetite-suppressing effect has been getting weaker, and my cravings are starting to come back — whereas before, I had no desire to snack at all.

Has anyone tried to take a few weeks break to help reset or at least reduce tolerance? Or maybe should I just switch to another compound like tirzepatide or retatrutide, but I'm afraid I might develop the same tolerance again, and possibly even faster, since my body is already used to semaglutide.
 
Tolerance is real.

Psychological first because you get used to a certain level of effect (so the first times when it was stronger seem weak to you now)

But also inside your brain / body and the signals that semaglutide sends (to put it simply as an explanation)

Taking a break is the first really good strategy. 4 weeks minimum before resuming a lower dose, to gradually increase the dose again.

If nothing satisfies you after that, tirz or reta can be more beneficial.
Because it also stimulates other receptors linked to hunger and digestion.
It doesn't necessarily make them stronger. But more versatile in the long term. Especially since we each respond differently to GLP1/glucagon/GIP signal.

And of course... Products aren't everything. Work on yourself and your relationship with food.
 
Hi, I have quite a bit of experience with GLP1s, tolerance is indeed real, with semaglutide I’d be careful going above 2mg a week as the side effects can begin to stack.

For myself I found that alternating between semaglutide and other compounds helps a bit, for example, 2 weeks sema, 2 weeks tirze etc, or even stacking them with an alternating schedule.

I couldn’t find much supporting this in terms of data other than anecdotal evidence, it might as well be placebo effect, as hunger drive is deeply intertwined with psychology, but it worked pretty well for me.

Best of luck!
 
In fact, I've heard similar feedback about tolerance. It's no coincidence that the official instructions for Ozempic suggest a gradual increase in dosage from 0.25 to 2.4 mg.

However, I strongly believe that GLP-1 receptor agonists should be part of a comprehensive fat-burning regimen rather than the sole focus. Therefore, I consider semaglutide to be a temporary boost that provides additional results without overtaxing the central nervous system or relying solely on willpower. However, it is recommended to avoid using it for an extended period. This is tool for self motivation boost.
 
As they have already mentioned, tolerance comes sooner or later, but it has come to you very early. Just one year and you already use 2.5 since??? Maybe you should have had more patience with the dosage increases.

For this, the only thing is to spend a few months at 0 and start over, but unfortunately, you will surely develop tolerance again, and each time sooner...

Some might think that it's also a good idea to switch to Retatrutide and try it, which, as we know, is a triple agonist and works on the GLP-1R, GIP-R, and glucagon (GCGR) receptors. Structurally, it is very similar to Tirzepatide, which they mentioned above.

I haven't tried it yet, but from what I've seen in the studies (the FDA approval process is not yet finalized), it is a modified GIP molecule with 39 amino acids, although with significant changes in the structure of the amino acids, which allows its activity on the GCGR.

It seems to be 8.9 times more potent in GIP-R than in human GIP, agonizing much more than Tirzepatide in GIP-R, = more potency on GIP-R and perhaps also on GLP-1.

Moreover, it is 2.9 times less potent than human glucagon and 2.5 times less potent than human GLP-1. Therefore, this drug is an unbalanced GIP agonist, but at the same time, it is balanced when comparing the activation of GLP-1 and GCGR, which seems interesting for several reasons. Fewer side effects at the beginning of the regimen, fewer effects on the cardiovascular system, and the improvement in the interaction between the GLP-1 receptor and GCGR, which is interesting for the reduction of "internal organ fat, improving among other things fatty liver."
 
Baugaros said:
As they have already mentioned, tolerance comes sooner or later, but it has come to you very early. Just one year and you already use 2.5 since??? Maybe you should have had more patience with the dosage increases.

For this, the only thing is to spend a few months at 0 and start over, but unfortunately, you will surely develop tolerance again, and each time sooner...

Some might think that it's also a good idea to switch to Retatrutide and try it, which, as we know, is a triple agonist and works on the GLP-1R, GIP-R, and glucagon (GCGR) receptors. Structurally, it is very similar to Tirzepatide, which they mentioned above.

I haven't tried it yet, but from what I've seen in the studies (the FDA approval process is not yet finalized), it is a modified GIP molecule with 39 amino acids, although with significant changes in the structure of the amino acids, which allows its activity on the GCGR.

It seems to be 8.9 times more potent in GIP-R than in human GIP, agonizing much more than Tirzepatide in GIP-R, = more potency on GIP-R and perhaps also on GLP-1.

Moreover, it is 2.9 times less potent than human glucagon and 2.5 times less potent than human GLP-1. Therefore, this drug is an unbalanced GIP agonist, but at the same time, it is balanced when comparing the activation of GLP-1 and GCGR, which seems interesting for several reasons. Fewer side effects at the beginning of the regimen, fewer effects on the cardiovascular system, and the improvement in the interaction between the GLP-1 receptor and GCGR, which is interesting for the reduction of "internal organ fat, improving among other things fatty liver."
Click to expand...
Thanks for your informative answer. When it comes to drugs and medications, I’ve always developed a rapid tolerance to many of them, as if my body adapts very quickly to exogenous modifications.

Here I made the decision to stop semaglutide for 3 months and will start again with tirzepatide at a low dose. As SalvatoreCorvus mentioned, it’s psychologically tough but not impossible. I’ll stay just slightly above maintenance while eating clean (with the occasional cheat meal, like dining out). Anyway, thank you for your well-researched response. I might consider retatrutide later on, but for now I prefer to take things step by step.
 
Einherjar said:
In fact, I've heard similar feedback about tolerance. It's no coincidence that the official instructions for Ozempic suggest a gradual increase in dosage from 0.25 to 2.4 mg.

However, I strongly believe that GLP-1 receptor agonists should be part of a comprehensive fat-burning regimen rather than the sole focus. Therefore, I consider semaglutide to be a temporary boost that provides additional results without overtaxing the central nervous system or relying solely on willpower. However, it is recommended to avoid using it for an extended period. This is tool for self motivation boost.
Click to expand...
I very much agree. Whenever I dabble with GLP1s or use them with my clients, it's never a crutch to rely on, it's the last resort towards the end of a cut to ensure everything happens as we planned. I hope the original poster's semaglutide use is "recreational", not doctor prescribed for diabetes, if it is, then he should consult with them how to reset tolerance
 
Ich habe mit 0,25 mg auf 0,5 mg Erhöht und habe vom 31.1.2025 bis jetzt 32 kg abgenommen. Aber noch mal 5 Ampullen bestellt
 
Sanerfüger said:
Ich habe mit 0,25 mg auf 0,5 mg Erhöht und habe vom 31.1.2025 bis jetzt 32 kg abgenommen. Aber noch mal 5 Ampullen bestellt
Click to expand...

What's your %BF overweight?

30 kilos in 6 months with 0.25/0.50 mg of Semagutide is a spectacular number...What calorie deficit and dietary macros did you have for those numbers? You must have sacrificed a lot of muscle mass, that's for sure.

Could you indicate your starting weight, current weight, and final goal?

Thank you.
 
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ltts said:
Thanks for your informative answer. When it comes to drugs and medications, I’ve always developed a rapid tolerance to many of them, as if my body adapts very quickly to exogenous modifications.

Here I made the decision to stop semaglutide for 3 months and will start again with tirzepatide at a low dose. As SalvatoreCorvus mentioned, it’s psychologically tough but not impossible. I’ll stay just slightly above maintenance while eating clean (with the occasional cheat meal, like dining out). Anyway, thank you for your well-researched response. I might consider retatrutide later on, but for now I prefer to take things step by step.
Click to expand...

I forgot to mention this... But assuming we're talking about reducing hunger to lose weight (not as insulin therapy).
There are studies on the synergies between Sema/Trize/Retra+Cagrilintide... It seems that hunger pangs disappear exponentially.

If the primary goal is anorexogenic, and you're willing to lose muscle due to lack of nutrients...Perhaps instead of taking breaks from Tirze, it would be interesting to combine it with Cagri to obtain the synergies.

Novo Nordisk is already in Phase 3 of the trial with CAGRISEMA, and it seems to improve appetite loss, but increases negative effects such as nausea, vomiting, etc.

We'll have to wait to see what the results of the long-term studies are.

Regards
 
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