Tolerance reset

SoCalGirl said:

LOL - MATH IS HARD! @woundcarping I will NEVER let this go!

Lady J - what's your target amount of weight to shed? I'm 100% with you on the new wardrobe! Here in Los Angeles it just dipped under 72 degrees, so out came my treasured DULUTH double-lined cargo jeans from last year - no way am I freezing. I pulled them up, zipped them, and down they went. My feelings are VERY conflicted...

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This morning the scale showed 164. Given my height of 5'6, the metrics suggest dropping ten lbs would put me in the "normal" range. Honestly, at this point I'm not bothered either way and 164 would suit me fine. I won't claim to be big boned, though my rib cage is unusually large (which helps a lot with singing), and I carry a decent amount of muscle. Still, what's the harm in shedding a little more before switching to maintenance? Especially since I'm in perimenopause, my plan is to go for those ten pounds while also ramping up the resistance and strength training that used to be part of my everyday routine, but has largely fallen away in recent years, since I'm no longer working as a professional horse person. And as I've mentioned several times lately, the glps make weight loss feel achievable and sustainable at the same time.

Reta has been part of my routine for 10 weeks. Weight loss wasn't the reason I started, though being 17lbs lighter certainly isn't a bad side effect. My real goal was getting the wine under control. I simply struggled to stop once a good bottle was open. For that purpose, it performed really well. Several procedures are now scheduled that I honestly didn't expect to come through this year, so my plan is to begin again next year.

My dose stayed at just 1Mg weekly, and I'm curious what happens after a 12 week pause. Reta reduced my appetite for both food and drink, but I'm well aware that a good wine really calls for good food alongside it. So when there's no wine, there's no additional eating either.

I'd reached the tail end of my cut, and back when I used to do longer fasts regularly, it had been about a year since my last one. So my plan was to wrap up the cut by fasting for 4 days on nothing but black coffee, water and electrolytes.

And wow, whatever the extended fast did, it seems to have amped up my glps and apparently reset my tolerance, because I'm now dropping my dosage by a lot just so I can get enough food in. Could be a fluke, or it might be something to use down the road?

FunkyWhales78 said:

Since you're in maintenance now, has your tolerance pretty much held steady?

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Yeah, that's right. My maintenance dose is higher than what most people on here would even consider going up to, at 6 and 8mg.

Estarossa19 said:

What was your length of time on the 10mg dose prior to making the choice to go down in titration?

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I believe it was 3 or 4 weeks. I just realized one of my spreadsheets has gotten messed up — names and amounts are suddenly gone. This really sucks and it'll piss me the fuck off if it stays that way. I have no idea what could have caused it.

ladyj779 said:

Honestly, I feel like I've come out ahead — the only things I've experienced are pounds coming off and better health across the board, plus a general sense of being happier.

As for what it costs me, that would be buying new clothes.

My days are packed from morning to night, so for years now I've kept everything on a Google calendar with notifications turned on. Peps are simply one more entry on that list.

There will always be a reason someone can find to put their own health and well-being last. What people need to hear is that they are absolutely worth prioritizing.

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Same here, the only thing either of us had was the elevated RHR.

Flash-BCR said:

In my case (and probably plenty of others?) the unwanted effects fade away... what's left is simply the peptide pastime itself....a "pastime that pays off"...

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The RHR was one thing, and that went back to normal after 40 weeks.

Foggy-Hollow said:

There are several obstacles I could name, but honestly the one that matters most in my case is adverse effects. Right now I'm easing back onto tirz with tiny doses.

Once SI began intruding and that isn't typical for the kind of MDD I usually have, sema turned into an absolute no.


No sarcasm intended: Share the encouragement and the love. Big Pharma should go bankrupt. People NEED to look after themselves better. Just try not to frame it as somebody failing to care for themselves because they aren't on a Glp-1. At times it's a hard no that our bodies hand us.

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Hmmmm, I'm not really sure how to break this to you: without Big Pharma, there wouldn't be a single one of us sitting here today. Where do you figure the research comes from, and the products that the whole GRAY market then copies? Speaking as somebody who ended up in the hospital while pregnant because my asthma spiraled out of control, I have to say it: I am EXTREMELY thankful for Big Pharma.

Nobody wants to lose a baby because they can't breathe, and that has nothing to do with doing a bad job of looking after yourself.

There are people who are genuinely born with conditions that Big Pharma is able to help with, cure, or wipe out.

That said, if they'd just sell me my GLP-1 at a fair price, that would be a whole different conversation.

This is a topic where real data is genuinely needed. I get why so many folks in this community never want to stop taking the medication — I'm a big fan of it myself. Still, it would be helpful to have some idea of what lies ahead.

For maintenance I take tirz 15mg, reta 8mg, and cagri 0.5mg. I only began using GLPs once I had already dropped almost all of the 81kg I lost, so their only purpose is to stop weight regain and curb hunger.

betterathalo said:

This is a topic where real data is genuinely needed. I get why so many folks in this community never want to stop taking the medication — I'm a big fan of it myself. Still, it would be helpful to have some idea of what lies ahead.

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Because so many people have now come off GLP medications, and because formal research is still thin, the picture of what happens afterward is fairly clear: stopping the drug entirely also stops the advantages. Around 80% of people who quit GLP drugs put weight back on. Most of them recover roughly 60% of it in the space of a year. Compared with those who shed pounds through non-GLP means, they put it back on faster, and a bigger share of that regained weight is fat stored around the abdomen. On the whole, most will end up holding onto a loss equal to 5 - 25% of where they started.

Naturally, some do manage to keep the weight off. A few simply have good fortune and don't have to work very hard at maintenance. For most, however, holding the line takes a great deal of time and effort, and it will have to continue indefinitely. They have altered their eating habits as needed, and they have grown used to a lasting calorie deficit and to feeling hungry.


https://www.bmj.com/content/392/bmj-2025-085304

Gearhead73 said:


How long do you think it would take for someone on high doses (12mg+/wk) to completely reset their tolerance?

I would think that if I was at those dosages I would want to attempt resetting my tolerance to a starting dose after I reached my goal weight. It would probably be difficult to not gain a lot of weight back after going cold turkey, but if you could hold the fort down for a few months... you could have a much lower/cheaper maintenance dose.

My guess (based on nothing) would be 3 months.

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What makes you believe the drug has stopped working for you? Before any of this, have you ever dropped weight through nothing but eating less and moving more? You probably recall that each pound you shed made the next one harder, and your hunger kept climbing. That's just how the body normally reacts to losing weight, isn't it? It's the body's defense mechanism, or at least its attempt to push us into doing what's necessary so we don't waste away and die of starvation. Clearly, in our case it misfires a bit.

Still, you can picture how that rising appetite, that crumbling willpower, and so on… how those things could work directly against what your GLP-1 medication is trying to accomplish?

Truthfully, it's unfortunate that these drugs don't quit working. If they did, and people stalled out because the medication was no longer effective, then quitting it and keeping the weight off would be easy. After all, there's no reason to keep taking a drug that isn't giving you a therapeutic benefit. But we all know what tends to happen to most people once they stop GLP-1s. The drug leaves the picture, the appetite remains, like a lamb to slaughter.

What your body is fighting back against is the weight loss, not the drug.

Staying at your goal weight instead of stopping for the next 6 months to a year will accomplish much more for "tolerance" than quitting reta would, since needing a higher amount isn't the same thing as classical tolerance. When you escalate the dose of reta, what you're really doing is battling your body's wish to put the weight back on, not dealing with a drug that has become weaker.

Take many substances, caffeine for example: you consume more, and to keep things balanced your cells alter their receptor count, so a larger amount is required for the same result. That is tolerance. With GLP1s, receptor count barely shifts.

What actually happens instead is that as the weight comes off, your body produces less leptin and more ghrelin, and both of those shifts leave you hungrier. Eventually your natural set point will reset, though that can take well over a year.

AngieHolmes said:

Because so many people have now come off GLP medications, and because formal research is still thin, the picture of what happens afterward is fairly clear: stopping the drug entirely also stops the advantages. Around 80% of people who quit GLP drugs put weight back on. Most of them recover roughly 60% of it in the space of a year. Compared with those who shed pounds through non-GLP means, they put it back on faster, and a bigger share of that regained weight is fat stored around the abdomen. On the whole, most will end up holding onto a loss equal to 5 - 25% of where they started.

Naturally, some do manage to keep the weight off. A few simply have good fortune and don't have to work very hard at maintenance. For most, however, holding the line takes a great deal of time and effort, and it will have to continue indefinitely. They have altered their eating habits as needed, and they have grown used to a lasting calorie deficit and to feeling hungry.


https://www.bmj.com/content/392/bmj-2025-085304

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Yeah, but that isn't what we're asking. What we want to know is how tolerance will look after spending different amounts of time off the medication. For example, if I go 2 months without taking it, how will I feel once I start again?

If data exists on that, great. It's just that I haven't seen it talked about much, since most people in this sub want to stay on it forever. Which makes sense.

betterathalo said:

Yeah, but that isn't what we're asking. What we want to know is how tolerance will look after spending different amounts of time off the medication. For example, if I go 2 months without taking it, how will I feel once I start again?

If data exists on that, great. It's just that I haven't seen it talked about much, since most people in this sub want to stay on it forever. Which makes sense.

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My sense is that the main thing here is gratitude: those who struggled with food noise and weight are relieved to finally have a medication that changes how their brain and body work.

That matches the overwhelmingly positive feedback I've seen in this community.

On the stopping-and-starting question, here's what comes up most often:

Weight gain is likely, food noise comes back, and this time your body composition will carry more fat.

Of course there are always exceptions- particularly the extreme athletes who concentrate on building muscle both during and after use.

Here is a recent study:

According to a new preclinical study from researchers at the Perelman School of Medicine at the University of Pennsylvania, inconsistent use of certain GLP-1 weight-loss medications, such as Ozempic and Wegovy, may significantly lessen their effectiveness. Published in the Journal of Clinical Investigation Insight, the study showed that each time overweight mice stopped and restarted GLP-1s, they dropped less and less weight compared their original weight-loss.


https://www.pennmedicine.org/news/stopping-and-restarting-glp1s-may-make-it-less-effective

when they talk about it "becoming less effective," do you know whether that refers to putting weight back on, or to the drug no longer working as well after you've been off it for a few months?

and don't take this as me judging anyone who chooses to stay on it. heck, i could end up being one of them.

A lot of the conclusions people pull from the data share one flaw: they rest on the "average" subject or on lab rats.

If someone stopped their GLP1s for months, I'd bet a good number of people — maybe even most — would put a meaningful amount of fat back on. That goes double for anyone who has never managed to lose weight successfully except with their GLP1s. Still, there are those who have already beaten their food demons and who use GLP1s simply to make the weight loss easier. Speaking as one of them, I'd really like to see more tolerance data.

That said, most of that second group hasn't pushed their titration as high either. So it may be a moot point — but I'm still curious.

betterathalo said:

Yeah, but that isn't what we're asking. What we want to know is how tolerance will look after spending different amounts of time off the medication. For example, if I go 2 months without taking it, how will I feel once I start again?

If data exists on that, great. It's just that I haven't seen it talked about much, since most people in this sub want to stay on it forever. Which makes sense.

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Look at what I wrote back to Skidude.

Skidude said:

My sense is that the main thing here is gratitude: those who struggled with food noise and weight are relieved to finally have a medication that changes how their brain and body work.

That matches the overwhelmingly positive feedback I've seen in this community.

On the stopping-and-starting question, here's what comes up most often:

Weight gain is likely, food noise comes back, and this time your body composition will carry more fat.

Of course there are always exceptions- particularly the extreme athletes who concentrate on building muscle both during and after use.

Here is a recent study:

According to a new preclinical study from researchers at the Perelman School of Medicine at the University of Pennsylvania, inconsistent use of certain GLP-1 weight-loss medications, such as Ozempic and Wegovy, may significantly lessen their effectiveness. Published in the Journal of Clinical Investigation Insight, the study showed that each time overweight mice stopped and restarted GLP-1s, they dropped less and less weight compared their original weight-loss.


https://www.pennmedicine.org/news/stopping-and-restarting-glp1s-may-make-it-less-effective

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There's also the drop in BP, the lower A1C, the lower Cholesterol and the improvement in Fatty Liver to keep in mind. Resting Hr returns to baseline somewhere around 38-40 plus weeks. At this stage, nobody can say what else might come up. Unless something harmful appears, I'm not getting off it. Heaven knows I've got plenty of reasons. That's where I stand and what I'm doing. Once my wife reaches that point, she'll be on it as well.

Gearhead73 said:

A lot of the conclusions people pull from the data share one flaw: they rest on the "average" subject or on lab rats.

If someone stopped their GLP1s for months, I'd bet a good number of people — maybe even most — would put a meaningful amount of fat back on. That goes double for anyone who has never managed to lose weight successfully except with their GLP1s. Still, there are those who have already beaten their food demons and who use GLP1s simply to make the weight loss easier. Speaking as one of them, I'd really like to see more tolerance data.

That said, most of that second group hasn't pushed their titration as high either. So it may be a moot point — but I'm still curious.

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For whatever reason, it looks like a lot of folks won't move beyond 4mg, though that's neither my problem nor my worry. I had reached 10mg when I made the call to step down to a maintenance dose. Honestly, my maintenance dose sits above what most people here seem to call a high dose these days. I'm fairly certain @Skidude is on a high maintenance Tirz dose.

BNLFL said:

Look at what I wrote back to Skidude.


There's also the drop in BP, the lower A1C, the lower Cholesterol and the improvement in Fatty Liver to keep in mind. Resting Hr returns to baseline somewhere around 38-40 plus weeks. At this stage, nobody can say what else might come up. Unless something harmful appears, I'm not getting off it. Heaven knows I've got plenty of reasons. That's where I stand and what I'm doing. Once my wife reaches that point, she'll be on it as well.


For whatever reason, it looks like a lot of folks won't move beyond 4mg, though that's neither my problem nor my worry. I had reached 10mg when I made the call to step down to a maintenance dose. Honestly, my maintenance dose sits above what most people here seem to call a high dose these days. I'm fairly certain @Skidude is on a high maintenance Tirz dose.

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yep, I'm now heading into year 3 of using this stuff..

sitting at 15mg for roughly 16 months.

I quit getting any response once they stopped caring about the studies or the facts.

Skidude said:

My sense is that the main thing here is gratitude: those who struggled with food noise and weight are relieved to finally have a medication that changes how their brain and body work.

That matches the overwhelmingly positive feedback I've seen in this community.

On the stopping-and-starting question, here's what comes up most often:

Weight gain is likely, food noise comes back, and this time your body composition will carry more fat.

Of course there are always exceptions- particularly the extreme athletes who concentrate on building muscle both during and after use.

Here is a recent study:

According to a new preclinical study from researchers at the Perelman School of Medicine at the University of Pennsylvania, inconsistent use of certain GLP-1 weight-loss medications, such as Ozempic and Wegovy, may significantly lessen their effectiveness. Published in the Journal of Clinical Investigation Insight, the study showed that each time overweight mice stopped and restarted GLP-1s, they dropped less and less weight compared their original weight-loss.


https://www.pennmedicine.org/news/stopping-and-restarting-glp1s-may-make-it-less-effective

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Those results are quite intriguing. Testing with a 2 weeks on / 2 weeks off pattern seems like an odd approach. Isn't the clearance period around 4-5 weeks? Perhaps it works differently in mice.

Even so, it does introduce at least a minor complication to how I was looking at things.

Gearhead73 said:

Those results are quite intriguing. Testing with a 2 weeks on / 2 weeks off pattern seems like an odd approach. Isn't the clearance period around 4-5 weeks? Perhaps it works differently in mice.

Even so, it does introduce at least a minor complication to how I was looking at things.

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Yeah, roughly the same duration as it takes to build up.

Gearhead73 said:

Those results are quite intriguing. Testing with a 2 weeks on / 2 weeks off pattern seems like an odd approach. Isn't the clearance period around 4-5 weeks? Perhaps it works differently in mice.

Even so, it does introduce at least a minor complication to how I was looking at things.

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Mice are a whole different story. The medication leaves their system far faster, and they shed the weight in a tiny slice of the time it takes us. With mice, everything moves fast. That's what makes them so convenient for research.

betterathalo said:

Yeah, but that isn't what we're asking. What we want to know is how tolerance will look after spending different amounts of time off the medication. For example, if I go 2 months without taking it, how will I feel once I start again?

If data exists on that, great. It's just that I haven't seen it talked about much, since most people in this sub want to stay on it forever. Which makes sense.

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I can't vouch for how solid that data is, but it does exist. What it suggests is that if you stop a GLP and then start again after a break (around 2 months, if I remember right?), you'll need a bigger dose and a slower climb back up before it works.