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Giant Semaglutide Thread (and other GLP-1 / GIP agonists)
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UncleBuns
Well-known Member
Side effects vary a lot. I get no fatigue even at 15mg a week.
Only sides I get from Sems and Tirz is indigestion. I take famotidine with them. No gastric slow down. No cramps. No other common sides as long as I increase dose appropriately. On the other end of the spectrum some people have their GI tract ruined by Sema.
You ask a lot of questions that see like you are trying to figure out how you will react to these but no one can answer that for you. Pick one, start low and titrate slowly. Take notes on the dosages, changes, positives and negatives and then you will know. If you start at recommended doing you will be fine. If you don't like it then just stop.
Ghoul
Well-known Member
Ok we need to straighten a few things out here.
With extraordinarily rare exceptions, Tirz has fewer side effects than Sema.
That's not up for debate, every clinician prescribing these drugs know this.
And "ruined GI tracts" from Sema is a load of bullshit emanating from some reddit hypochondriacs.
Things that don't happen:
Docs to tens of milllions of diabetics and overweight patients: "Here's your prescription for Ozempic/Wegovy. It's very effective, but it may ruin your GI tract.".
I personally am on 0.5mg Semaglutide and I have been for the last 8 months. I have no side effects apart from anhedonia, lower libido and occasionally my food noise returns by 10%.
I am hoping replacing Sema with 2.5mg Tirz OR 1mg Reta per week will improve upon that without giving me any additional sides.
I am concerned about GIP functions in fat cells to increase fat accrual.
Maybe I shouldn't be because all research indicates health is improved. I am also wondering how this will affect body composition over the long term.
Yesterday was my first dose of 2.5mg Tirz.
I chose Tirz as I believe it has a superior food noise reduction to Reta and doesn't increase RHR as much. I will be watching the research over the next few years.
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Ghoul
Well-known Member
There is ZERO evidence of Tirz increasing fat accrual. Tens of millions of patients using this compound for years. What do you think the odds are of no one, patients doctors, researchers noticing increased fat mass? Come on...
Nothing to worry about. For the overwhelming majority, Tirz shows greater weight loss, better body recomposition, and fewer sides.
Thank you, hopefully my experience will be good and I will report back.
Why do you think there is a GLP1 agonist coming out with a GIP antagonist component? This is the opposite to how tirz works. What do you think this change will achieve?
Also why do you think Eli Lilly reduced the GIP component in Reta vs their previous medication Tirz?
Ghoul
Well-known Member
Eli ran out of room on the peptide chain to include more of a GIP component. Not chemically, legally.
Sema is 31 amino acids. Tirz 39. Reta 39.
TLDR: an obscure part of Obamacare allows peptides over 40 amino acids to be copied by competitors almost immediately.
As a result, nearly all new peptide/protein drug development projects have been focused on sub 40 amino acid peptides, even when larger chains would make the drug better.
Ghoul
Well-known Member
Not to go too far off topic, but I'm reminded of this every time Bernie Sanders or Elizabeth Warren starts waving their finger around saying Ozempic should be $3 a month.
We have an imperfect, but functional balance between encouraging investors to spend billions, most of which goes into the trash, chasing long shot miracle drugs, and allowing them the possibility of hitting the jackpot once in a while, while benefitting us all from those developments.
Essentially, the developer of unique new drug gets to charge whatever they think the market will bear (too high and they won't sell much) for about 10 years.
Then a bunch of generic companies, that didn't have to pay to develop it, can make and sell it for as low as they can, to everyone's benefit, forever.
So the wealthy (that's most Americans with some form of drug coverage) get it first, what's new, and later everyone gets it as cheap as it can be made, with a small profit margin. Example: Provigil (Modafinil) $2,000/month on patent. Now $9/month generic. By the way, Ozempic goes generic in 5 years. Then we'll see pharma Semaglutide for $25/month. Tirz a few years after that.
Diminish the profit motive at our peril. We'll enjoy all the drug innovation the Soviets produced in labs full of risk averse government employees...
Me? I fucking love Big Pharma.
Very interesting.
I read
both agonism and antagonism of GIP have metabolic benefits for 'reasons'.
One idea is that the agonist is acting as a “functional antagonists” by desensitising GIPR.
So theoretically both agonism and antagonism could have benefits.
Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?
Abstract. Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mous
academic.oup.com
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Ghoul
Well-known Member
We always have to keep in mind despite the long track record of humans using this this class of drugs, the best evidence for safety, there's a long, long way to go in understanding all the effects, By which we're really looking at the effects of what had been a somewhat obscure natural metabolic hormones, GLP and GIP.
To answer your question, here's one possibility Tirz will help with your goals, even lowered to a non-weight loss dose (just keep lowering until you stop feeling appetite suppression, but keep in mind, it takes 4 weeks to fully adjust to a new dose).
I'm basing this theory on recent, very early "low powered" research into this area:
A study on some diabetics (of course) found that Tirz:
-Did NOT increase resting metabolism.
-DID significantly increase fat oxidation and reduced protein oxidation, compared to subjects not using Tirz in a caloric deficit.
They didn't speculate in the mechanism of action that caused this positive effect on recomposition, but I will.
Seperate animal studies showed that Tirz increased the expression of certain genes in Brown Adipose Tissue, boosting thermogenesis, ie, the ability of brown fat to oxidize fats to keep internal organs warm. It's been observed "naturally thin" and underweight people have greater Brown Adipose Tissue mass that's also more reactive than normal and overweight subjects.
Here's the killer part of this, if it holds up in future research. The effect is CUMULATIVE. The longer one is treated with Tirz, the greater the increase in thermogenic capability becomes.
Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue - PMC
Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies ...
pmc.ncbi.nlm.nih.gov
So, for that reason among others, if I were in your shoes, on a bulk, just keep the Tirz dose below where you feel appetite suppression. There's no reason to believe appetite suppression is required for the other aspects of these drugs to work. In fact, at a "maintenance" dose, the balance between weight and dose, you should feel nothing. It's neutral with regard to appetite and side effects. 15mg Tirz and I feel nothing. It didn't stop working, that's how it's supposed to work, and I'm confident the other metabolic improving effects continue.
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Thank you. I always love your informative posts.
Is that why Tirz users complain about being cold? Do you think this effect will work on tiny dosages? The diabetics used the maximum dose of 15mg.
Ghoul
Well-known Member
Given how safe Tirz is I think there's plenty of potential reward to outweigh any risk.
Whatever amount of GIP you naturally release, Tirz adds a "floor" of continuous GIP, with natural GIP pulses building above that.
So I think that even a low dose may keep this process of cumulative improvement of BAT function going.
On balance, even though taking a GLP while in a bulk may seem counterintuitive, there don't seem to be any downsides we've identified, or even hinted at, and numerous potential upsides as we wait for more research to shed more light on this.
You're just putting yourself into "GLP maintenance phase", where users appear to benefit from continuing health benefits not entirely accounted for by weight loss.
Instead of getting there by lowering weight to match the dose, you're lowering the dose to match your (higher) goal weight.
(as far as "always cold" I think it comes from the same cause of. fatigue. The sudden drop in calorie intake, faster than the body can acclimate to it. Both effects, are, in my experience, temporary. One negative effect of the self treating GLP scene is a rash of impatience, never giving these drugs a chance to work properly, changing up protocols and compounds, probably inducing so many sides, and maybe "breaking." their ability to properly respond to these hormones, never reaching the "maintenance" phase.)
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UncleBuns
Well-known Member
"Ruin" I don't mean permanent. I mean bad enough GI sides that they can't take it.
Ghoul
Well-known Member
Oh yes for sure. Brutal GI sides are entirely possible, especially with Sema. I think they can be avoided by being very careful not to eat "beyond your hunger", especially when starting or increasing the dose. In my experience, the physical limitations on food intake, and the "punishment" (nausea, acid reflux) for eating too much, come before the appetite suppression. kicks in. zap you've got to anticipate it and eat just until appetite is satisfied and stop. Wait at least another hour before eating again. Staying. hydrated, and a glass of Metamucil fiber daily can help a lot.
The latest guidance tells doctors to be vigilant for the worst sides from week 4 to 8 for Sema, and week 2 to 4 for Tirz.
That said, quite a few folks have been hospitalized after taking 20x the intended dose, 5mg instead of .25mg and while very uncomfortable, they always recover in a few days without permanent damage.
I’ve found as long as my diet is lower in fat I don’t get the nausea. I’ve wondered if GLPs may end teaching people how to eat long term since you and up eating pretty clean to avoid side effects.
Ghoul
Well-known Member
It's definately a teacher.
It eases the intense desire to eat, but ignore appetite signals, only eating when hungry, and stopping when satiated, and you will be punished.
That's why I laugh at people who suggest that those who've been successful with GLP "haven't changed anything and just want go keep eating crap". High fat foods make things worse. Sweet food loses its appeal.
Whenever I hear of people suffering frequent side effects, I assume they haven't. "gotten it" yet and keep eating out of habit, not hunger. Of course a complete lack of education of what to expect by most prescribers doesn't help.
Ghoul
Well-known Member
I'll start by saying you don't even realize it's there until it stops. You feel a sudden, dramatic, unexpected change, Something that's always been there, suddenly goes quiet. Only coming back when you legitimately need to eat.
Here's the best parallel I can make.
When you feel hunger, and for whatever reason, can't address it, and time keeps passing but you can't get any food, the preoccupation with eating intensifies until it's all you can think about.
Your mouth literally waters at the thought of food.
The smell of something cooking draws your attention much more than if you weren't hungry.
You aren't going to be able to pay attention to other subjects and become completely preoccupied with getting something to eat.
Most people get increasingly irritable, angry even. I'm sure you've seen this mood change in people, even animals. I think it's why so many women carry snacks with them lol.
Post Thanksgiving feast, the opposite happens. Food no longer seems palatable. The thought of another bite makes you feel ill. Your favorite foods hold no appeal whatsoever.
All of this has a biological basis (GLP's impact on the hypothalamus playing a major role).
The current hypothesis is that increasingly people aren't producing sufficient GLP hormone or have developed insensitivity to it, like insulin resistance.
Bariatric surgery, which shrinks the stomach, induces weight loss because when the stomach stretches, GLP receptors are released, increasing sensitivity to GLP, quieting "food noise", aka, the drive to eat.
You can easily overlay this to other compulsive behaviors. Cigarette smokers experience this in the absence of nicotine, getting crankier and more desperate the longer they go without, alcoholics as well, opioids, cocaine, you name it all experience something similar in the absence of whatever is being craved.
It's no coincidence GLPs look like a potent treatment for all of these addictions. They all influence behavior via the malfunctioning of this psychological "noise" mechanism, that GLPs, normally released after eating, shuts down.
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Food noise is a colloquial term. It refers “to the constant thoughts or recurring ruminations about food which could contribute to overeating
@Ghoul
Have you noticed heavier people need higher dosages of these drugs?
“Body weight was the most important covariate for Semaglutide exposure, showing decreased exposure with increasing body weight.”
Ghoul
Well-known Member
Actually no I haven't. It's density of GLP receptors that makes the most difference, which is primary determined by genetics, and sex (men generally have a far higher density). Some huge people have a potent reaction to small doses, and some small folks don't react at all until nearly the max doses are reached.
The Mayo Clinic developed a genetic test that can predict the reaction to GLPs by what your genes indicate about receptor density and glp production factors.
Hungry Gut :: Phenomix Sciences
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