Before the raise of glp1 people used to run other compounds to lose weight. Personally i dont even care about eating on extended release methylphenidate, thats why i even stopped taking it. There is also the famous eca stack with ephedrine. Medicine like mysimba or adipex. Considering that glp1 give kind of fast tolerance and get expensive quick shouldnt more "simple" options like stimulants be considered ?
MESO-Rx
Anabolic Steroids
Stimulants as weight loss drugs
- Thread starter MrCloud
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Biggerisbetternl
New Member
Every drug has its pro's and cons. From what I understand the sides from stims are a main drawback. GLP-1 drugs are actually designed for weight loss and should give users less negative sides. Besides that the stims like ephedrine you mention are banned or illegal in most countries so not much safer in that regard either. Caffeine is a stim too that can aid with weight loss, and is probably the one of the few I would recommend if you have to go that route.
Unfortunately you dont make much sense
yeah ephedrine is banned because they used to make amphetamine out of it. In my country you can still find it otc in pharmacy for nasal congestion.
They target GPCRs that undergo the same internalization as any other. To say they don't create any tolerance is just false.
Some are resistant sure, especially Orforglipron, but not immune.
why are people looking at past shitty alternatives? just use reta. one of my mates has been on it for 2 years and while it's true he now takes 10mg a week it still works. And he is constantly sub 10% bodyfat.
Stimulants are shit for weight loss. You build tolerance fast on them. After a while I could eat even while on a high dose of stims. Stick to reta even if you take 10mg a week, is worth it!
Stimulants are shit for weight loss. You build tolerance fast on them. After a while I could eat even while on a high dose of stims. Stick to reta even if you take 10mg a week, is worth it!
Most of us here originally kept lean with the types of drugs you’re talking about. ECA, Clen, DNP, etc. Glps have only been prevalent in this game for 3-4 years now in general.
Stims are ok and work fine. But for overall, long term safety purposes, I think glp drugs are generally safer overall. But we still lack long term studies. I use glps to stay lean now and use mild stims for preworkout only.
I guess I agree with you but you seem to be coming from a closed mind not considering most of us are over 22 and been lifting more than a year or two so we have plenty of experience with stims over the years.
Stims are ok and work fine. But for overall, long term safety purposes, I think glp drugs are generally safer overall. But we still lack long term studies. I use glps to stay lean now and use mild stims for preworkout only.
I guess I agree with you but you seem to be coming from a closed mind not considering most of us are over 22 and been lifting more than a year or two so we have plenty of experience with stims over the years.
SlamSumTest
Member
There’s no such thing as free lunch and everything has a cost.
My results on Reta have been amazing, to the point where getting lean/ripped finally became effortless…which concerns me.
I’m a bit suspicious of how GLP1s tamper and down regulate your dopamine pathways. While people are able to quit addictions, I do believe this does more harm than good for everyone else.
But, at the end of the day, all of these drugs must be used indefinitely to maintain the results achieved on it. Take that what you will, we don’t really know how tampering with our reward pathways can cause issues down the line (mostly psychological issues potentially if I had to guess).
My results on Reta have been amazing, to the point where getting lean/ripped finally became effortless…which concerns me.
I’m a bit suspicious of how GLP1s tamper and down regulate your dopamine pathways. While people are able to quit addictions, I do believe this does more harm than good for everyone else.
But, at the end of the day, all of these drugs must be used indefinitely to maintain the results achieved on it. Take that what you will, we don’t really know how tampering with our reward pathways can cause issues down the line (mostly psychological issues potentially if I had to guess).
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SubparMarioBro
Member
They don’t actually.
(the entire paper is about this subject if you want to learn more)
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It depends on how you agonize the receptor. Semaglutide causes internalization from full agonist activity. Tirzepatide and Retatrutide have biased agonism towards camp signaling, which makes them less likely to develop tolerance. Orforglipron avoids it almost entirely.
If these drugs didn’t develop tolerance people wouldn’t have to titrate them upwards over six months, it’s that simple.
If you need some sources that prove this though
JCI Insight - Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
JCI Insight - Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist - PMC
In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist - PMC
SubparMarioBro
Member
The GL0034 paper you linked explicitly argues against your claim that semaglutide causes more desensitization than a biased agonist like GL0034. They even tested that hypothesis for you:
“In case GL0034 and semaglutide differed in their ability to desensitize the GLP‐1R, we also measured insulin release after overnight incubation of INS‐1832/3 cells with a range of concentrations of each agonist; responses were virtually indistinguishable between the two compounds (Figure 2C, Table 1). These data demonstrate that, as expected, GL0034 is capable of potentiating insulin release at elevated glucose concentrations, but do not provide evidence of an increased insulinotropic effect of GL0034 compared to semaglutide.”
They explain that GL0034 is more potent molecule for molecule because of its increased selectivity for cAMP, not because semaglutide has reduced efficacy due to desensitization mechanics. They go on to explain that part of the reason semaglutide performs well is because receptor recycling occurs more quickly with semaglutide than a biased agonist like GL0034, which argues against the idea that biased agonists avoid desensitization. If you’re going to use papers as proof, they shouldn’t be explicitly rejecting the mechanism you’re claiming.
The tirzepatide paper is focused on characterizing tirzepatide and doesn’t get into the mechanics of how receptor desensitization might or might not effect semaglutide. They find (like the GL0034 paper) that the increased cAMP bias of their molecule provides a greater acute effect for a given level of receptor engagement but they don’t extend this into an evaluation testing and demonstrating the irrelevance of desensitization like the GL0034 paper did. While it doesn’t support your claims, at least the tirzepatide paper doesn’t go out of its way to explicitly debunk your hypothesis.
Your claim that the need for dose titration proves that these drugs cause tolerance is just wrong. Pharma gets good weight loss results when they slam people with the max dose of these drugs on day one, see Maritide as an example where they started people at the max dose. The problem is that starting people at max dose Maritide made the drug behave less like an incretin mimetic and more like a bulimia mimetic. Gradually increasing the dose is a mitigation strategy for those side effects, not because they need a higher dose to overcome drug tolerance.
It’s not surprising that higher doses cause more weight loss, higher dose -> larger effect is the basic idea behind the dose response curve. As weight is lost the body pushes back harder to resist further loss and promotes weight gain by increasing appetite and reducing energy expenditure. That’s been true for every weight loss method ever invented, you don’t need to invent a special story about “GLP-1 tolerance” to explain something that happens even without GLP-1s.
BP_6
Member
One very interesting thing I have noticed with GLP-1's that arguably can be just as good as the appetite suppression. My cravings for certain foods, I will use peanut butter as an example have been almost eliminated just like that. That literally has never happened before. That craving always existed even when I was not hungry and bulking in the past.
I don't drink or smoke, but I have heard reports from many people saying how it killed their craving for alcohol, smoking, and certain other vices. There obviously is more to this GLP-1 thing that just simple appetite suppression as I am sure they already know and are working on to isolate.
Modified versions of this drugs may in the future be able to help people with drug addictions and such. Kill their craving/desire for the drug vs just trying to substitute it with something a bit less harmful.
I don't drink or smoke, but I have heard reports from many people saying how it killed their craving for alcohol, smoking, and certain other vices. There obviously is more to this GLP-1 thing that just simple appetite suppression as I am sure they already know and are working on to isolate.
Modified versions of this drugs may in the future be able to help people with drug addictions and such. Kill their craving/desire for the drug vs just trying to substitute it with something a bit less harmful.
Quite disingenuous to use maritide as an example when it has a half life of 21 days. Take 5 half lives to steady state and even at max doses it is titrated over 3+ months.
Setmelanotide and Orforglipron are both effective with short half lives and no dose titration because the former doesn’t rely on GPCR and Orforglipron specifically avoids internalization.
Decrease your kcals, 250 a day. You could do Yohimbine to fasted cardio. When your weight los stabilised decrease another 250kcals to the max of your current BMR
SubparMarioBro
Member
It’s not disingenuous, it directly refutes your claim that dose increases are needed to counter “desensitization”. Clinical trials for Maritide not only titrated some groups over several months, they also had groups that started at the max dose with no titration. From a weight loss perspective it didn’t make much of a difference whether they titrated gradually or just pinned the full 420mg on the first day, but the side effects were bad enough that Amgen abandoned the no-titration idea after that trial.
And we’re back to making claims that are disproven not just by the papers I linked but the paper you linked as well. The GL0034 paper tested the hypothesis that semaglutide desensitized the receptor more than a biased agonist like GL0034 and found that it didn’t.
I have no idea why you’re bringing up a completely unrelated drug like setmelanotide or why you’re claiming that MC4R is not a GPCR. That’s just wrong, MC4R is in fact a GPCR.
I also have no idea where you got the idea that orforglipron has no dose titration. In clinical trials they started patients at 1mg and gradually increased their dose over several months (the 36mg group didn’t reach 36mg until month 6), but it’s funny that you’d pick one of the least effective GLP-1 agonists developed in the last decade as your example of the benefits of “avoiding internalization”.
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It’s disingenuous because the long half life means the drug is naturally titrated upwards at the same dose until steady state would be reached, over 3 months.
Setmelanotide functions through a GP independent mechanism via kir7.1 coupled closure. It’s not dependent on receptor sensitivity.
The articles I linked were solely used to show the internalization occurred. I see your article wasn’t arguing that though, so yes I was wrong there.
But, going all the back to the first argument, then if GIP is susceptible to internalization mediated desensitization then only solo glp1r agonists could be argued as having no tachyphylaxis.
And even so, they are susceptible to other CNS adaptations to delayed gastric emptying.
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