Anybody heard of Setmelanotide!!

[donpasscal]

Setmelanotide, sold under the brand name Imcivree, is a medication used to treat severe obesity caused by specific genetic defects, primarily affecting the melanocortin-4 receptor (MC4R) pathway. It's designed for individuals with genetic conditions like POMC, PCSK1, or LEPR deficiency. The drug works by activating the MC4R, a receptor involved in regulating appetite and energy balance, to promote satiety and reduce weight.

Key aspects of setmelanotide:

• Mechanism of Action:
  Setmelanotide is a melanocortin-4 receptor (MC4R) agonist. By activating this receptor, it helps regulate appetite and energy expenditure, leading to reduced food intake and weight loss.
  Indications: Setmelanotide is specifically indicated for the treatment of chronic weight management in patients with obesity due to confirmed deficiency of POMC, PCSK1, or LEPR.
  Dosage: The dosage of setmelanotide varies based on age and weight, with adjustments made by a healthcare professional. For example, children 6 to <12 years of age start with 1 mg injected subcutaneously daily for 2 weeks, and adults may start with 2 mg, potentially increasing to 3 mg as a maintenance dose, according to the Mayo Clinic.

• Administration: Setmelanotide is administered via subcutaneous injection.

• Side Effects: Common side effects include injection site reactions (pain, redness), nausea, and abdominal pain. Skin color changes (hyperpigmentation) can also occur.

• Monitoring: Patients taking setmelanotide require monitoring for depression and suicidal ideation, as these have been reported as potential side effects.

• Contraindications:

• Setmelanotide is not recommended for use in neonates or infants due to the presence of benzyl alcohol, which can cause adverse reactions, according to the National Institutes of Health.

• Important Precautions: Patients should be educated on proper injection techniques and the need to continue the medication regularly to maintain weight loss.
  

 

[Calm Logic]

Has anyone tried setmelanotide? Due to the cost, need for daily injections, and being less effective than cagri (for the general population), it seems only for long-term use if cagri did not work out in a stack (or for a different side effect profile):

Feature	Cagrilintide	Setmelanotide (General Population)
Pathway	Amylin Analog	MC4R Agonist
1yr Weight Loss	~11.8%	~7% – 10%
Skin Symptoms	None	Darkening / Hyperpigmentation
Dosing	Weekly	Daily

When does Setmelanotide make sense?

Non-Responders: If someone has high-level "GLP-1 resistance," they might have a defect further down the line in the MC4R pathway where setmelanotide acts.

Specific Hunger Profiles: For those with "bottomless" hunger (hyperphagia) that doesn't respond to the "fullness" signals of GLP-1s, setmelanotide’s direct action on the brain's hunger center can sometimes be the only thing that works.

As stated by the OP's post, it is injected daily, at least 2 mg per day. So a vial of 10 mg would only last five days (kit for 50 days). At 3 mg per day, 9 vials would be needed per month. I have seen it for $100/kit, which means a year's supply would be $730 (at 2 mg/day) or almost $1,100 (at 3 mg/day).

Some more info on the brand name, including $34k pricing (for a month's supply at 3 mg, or 9 vials of 10 mg each):

https://www.goodrx.com/imcivree

Comparison with MT-2, MT-1, and PT-141:

Melanocortin Peptides: Weight Loss, Cycling, & FDA Status
Estimates based on general population use (Non-Genetic)

Peptide	Receptor Targets	Est. Weight Loss	Cycling Strategy	Primary Safety Concerns
Setmelanotide	MC4R (Selective)	7% – 10%	Continuous (Daily)	Hyperpigmentation, Mood changes, Injection site pain.
MT-2	MC1R, 3R, 4R, 5R	5% – 8%	Cycled (5 on / 2 off)	Kidney stress, BP spikes, Mole changes, Rhabdo.
PT-141	MC3R, MC4R	1% – 2%	As-Needed (Pulse)	Severe Nausea/Vomiting, Acute BP spikes.
MT-1	MC1R (Selective)	< 1%	Seasonal / Periodic	Headaches, Skin lesion darkening, Flushing.

Chronic use of MT-2 is widely discouraged by medical experts due to its non-selective nature and the systemic "stress" it places on several organs.

 

[Calm Logic]

Good for breathing better too, from a 2025 article:

FDA-approved drug may help restore breathing in obesity-related sleep disorder

Researchers from the George Washington University have uncovered promising evidence in an animal study that shows setmelanotide, an FDA-approved medication for a rare genetic obesity disorder, may offer a pathway for treating a life-threatening form of sleep-disordered breathing called Obesity...

www.news-medical.net

"Setmelanotide improved breathing more than would be expected just from boosting metabolism, meaning it likely acts directly on brain regions that control breathing."

"This is the first direct evidence that the MC4R pathway plays a critical role in how the brain controls breathing in obesity. Setmelanotide may be able to treat Obesity Hypoventilation Syndrome by bypassing the leptin (a hormone made by fat cells that helps regulate breathing) which is common in people with obesity."

Good for mood as well:

Obesity: exploring its connection to brain function through genetic and genomic perspectives - Molecular Psychiatry

Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a “pure” metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present...

www.nature.com

Metreleptin, setmelanotide, and liraglutide have been associated with improved cognitive function and mood. This is not surprising as these drugs act on regions of the CNS linked to these brain functions regulation [69]. These findings confirm that obesity is not merely a disorder of energy imbalance but also involves complex neurobehavioral components. It also emphasizes the importance of evaluating the neurobehavioral and mental effects of obesity treatments during the clinical trial process and beyond.

 

[lessthanhalf]

It is approved for specific genetic causes of obesity where it directly interacts with the broken system to help fix it, and it does improve obesity in that syndrome and is used for that. What I could not find was any evidence of it being tested in the general population for obesity, I did ask chatgpt about this while ago , wondering why this was never tested and it seemed to think it would not work as well in people with normally working melanocortin receptors. The appetite regulation system is ridiculously complex and convoluted, with many redundant systems, which is essentially why it took 40 plus years of research to find anything that actually worked over the longer term - GLP's. Most drugs that interfere with that system do not reliably cause weight loss.

 

[Calm Logic]

I did ask chatgpt about this while ago , wondering why this was never tested and it seemed to think it would not work as well in people with normally working melanocortin receptors.

Yeah, if I tried setmelanotide, I would just buy a vial or two to see if I get some feelz and go from there. The side effects of setmelanotide may be appealing though, haha. Horny and tan. Maybe too horny (or nauseated) to be hungry?

My bro science, Freudian theory (partly based on a sliver of anecdotal evidence): since setmelanotide is most similar to MT2 (which also hits MC4R but is far less selective), it makes me think mood/cognition could be a factor in some non-genetic cases:

While MC4R is the primary target for weight loss, researchers are increasingly looking at MC3R and MC4R in the limbic system (the brain's emotional center).

MC3R (MT2): Linked to dopamine, reward, and "vigor." It is the "drive" receptor that contributes to the mood-boosting and libido effects.

MC4R (Setmelanotide): Linked to satiety but also the HPA axis (stress response). While it suppresses hunger, its activation is often associated with increased anxiety or "agitation" in the general population.

Setmelanotide is not a "pure" MC4R drug. In pharmacological testing, it shows about 20-fold less activity at the MC3R (and MC1R) than it does at the MC4R.

Translation: For every 20 "hits" it makes on your hunger-satiety receptor (MC4R), it’s landing about 1 hit on your reward/energy receptor (MC3R). Because the doses used for weight loss are relatively high and administered daily, that "1 in 20" activity is enough to cause measurable physiological effects.

According to Dr. Seeds, MT2 (which hits both 3R and 4R) is said to improve mood and libido somewhat for some, as a side effect. But the problem with MT2 (an "aggressive agonist" with a longer half-life) is that you can't take it for long.

So cyclical, low-dose, PT-141 (FDA approved for one thing for some women) can be better for long-term mood and libido enhancement, with PT-141 hitting the 3R and 4R receptors to some degree (without really targeting the 1R tanning receptor):

In anecdotal and clinical reports, the intense MC4R activation from setmelanotide can lead to a state of "agitated exhaustion." Overstimulating the HPA axis (the stress response) daily isn't the same as the "vigor" boost Dr. Seeds describes with low-dose, cyclical peptides.

Peptide	Primary Targets	Tanning (MC1R)	Mood/Libido (MC3R/4R)	Weight Loss	Best Use Case
MT2	1R, 3R, 4R, 5R	Extreme	High (Aggressive)	Very High	Short-term "Hammer"
MT1	Primarily 1R	High (Linear)	Low	Minimal	Pure Photoprotection
Setmelanotide	4R (Selective)	Moderate (1:20 Leakage)	Variable (Anxiogenic)	High	Genetic Obesity
PT-141	3R, 4R	Minimal	High (Targeted)	Low/Moderate	Sustainable Signaling

Protocol: Cyclical PT-141

Phase	Dosage	Frequency	Clinical Goal
1. Assessment	0.25mg – 0.5mg	Single Dose	Test nausea threshold & flushing response.
2. Titration	0.75mg – 1.0mg	2x per week	Identify "Sweet Spot" for mood & libido.
3. Maintenance	1.0mg – 1.5mg	Max 3x weekly	Sustainable signaling; avoid downregulation.

 

[Calm Logic]

On the negative side, setmelanotide is not as soluble as other peptides. A combination of BAC and some PEG (5% to 10% of total intended volume) seems ideally required for recon, with the PEG applied first. But PEG (polyethylene glycol) is itself an irritant which can sting/burn, including after injection:

https://www.sciencedirect.com/science/article/abs/pii/S0045206825012507

Despite considerable clinical efficacy, setmelanotide's therapeutic application is limited by two critical drawbacks: poor aqueous solubility, which necessitates the use of irritant PEG excipients and raises safety concerns [35], and inadequate MC1R selectivity, leading to dose-limiting skin hyperpigmentation that compromises adherence [36].

PEG is in the commercial drug version as well:

Imcivree (setmelanotide) contains N-(carbonyl-methoxypolyethylene glycol 2000)-1, 2-distearoyl- glycero-3-phosphoethanolamine sodium salt, commonly known as PEG-DSPE. This ingredient acts as an inactive excipient in the subcutaneous injection to help stabilize the formula

On the positive side:

Setmelanotide treats opioid-induced respiratory depression (in mice)

 

[Super Trips]

On the negative side, setmelanotide is not as soluble as other peptides. A combination of BAC and some PEG (5% to 10% of total intended volume) seems ideally required for recon, with the PEG applied first. But PEG (polyethylene glycol) is itself an irritant which can sting/burn, including after injection:

https://www.sciencedirect.com/science/article/abs/pii/S0045206825012507

PEG is in the commercial drug version as well:




On the positive side:

Setmelanotide treats opioid-induced respiratory depression (in mice)

so could you in theroy just use bac water? Im thinking of trying it out as cagri has now done nothing for me on my stack

 

[Calm Logic]

so could you in theroy just use bac water?

Right. Apparently no issues with just BAC for recon, according to one person on it.

But I haven't seen a single person vouch for it for weight loss. And a single 10 mg vial would last only 5 days at the most.

I think in theory the more mood/cognitive peps like PT-22-28 are just as likely/unlikely to help with weight loss.

 

[Super Trips]

Right. Apparently no issues with just BAC for recon, according to one person on it.

But I haven't seen a single person vouch for it for weight loss. And a single 10 mg vial would last only 5 days at the most.

I think in theory the more mood/cognitive peps like PT-22-28 are just as likely/unlikely to help with weight loss.

i got on that GB for the pt-22 hope that works better

 

[FlowerFairy]

I’m using set because it was recommended as a microdose to break a stall. Most using it this way take no more than 500 mcg daily due to sides, plus it’s effective at that dose. I take 250 mcg daily. First 5 days I had energy and motivation to burn- showed no weight loss because I doubled my step count plus was doing heavy yardwork.. I ached all over because I’d overdone it, but I still had the drive to keep working and walking. I actually gained 4 lbs due to muscle stress/microtears and water retention. I felt a little nausea on day 1, but it wasn’t enough to take anything other than tums. Other side effects can be leg pain/cramps due to magnesium deficiencies but I take my mag daily so it hasn’t been an issue. Oh, and since it’s related to Melanotan, it can cause tanning/freckling, but I’m so pale I can’t tell if it’s doing that yet. Once past the muscle recovery, I’ve lost the 4 lbs plus another 6. Nothing spectacular but it’s still encouraging. I’ll try to check in if anyone is interested but I’m bad at that lately.

 

[Calm Logic]

Setmelanotide Shows Limited Efficacy in Heterozygous Obesity Gene Carriers – Patient Worthy

patientworthy.com

The results across all four substudies failed to demonstrate statistically significant BMI reductions when comparing setmelanotide to placebo. Placebo-adjusted BMI changes ranged from just 1.7% for SH2B1 carriers to 4.3% for POMC/PCSK1 carriers—improvements that fell short of statistical significance thresholds required for regulatory approval.

 

[chmuse]

Right. Apparently no issues with just BAC for recon, according to one person on it.

But I haven't seen a single person vouch for it for weight loss. And a single 10 mg vial would last only 5 days at the most.

I think in theory the more mood/cognitive peps like PT-22-28 are just as likely/unlikely to help with weight loss.

One of my friends wasn't losing weight, even with a glp; she started losing- slowly, but finally losing, when she added set.

I won a kit in a fundraiser and want to try it, but haven't researched if it's okay to use with my current gluta/ss31 usage (especially since gluta and set have opposite effects on skin pigment)

 

[FlowerFairy]

One of my friends wasn't losing weight, even with a glp; she started losing- slowly, but finally losing, when she added set.

I won a kit in a fundraiser and want to try it, but haven't researched if it's okay to use with my current gluta/ss31 usage (especially since gluta and set have opposite effects on skin pigment)

Yeah.. I was using gluta and melanotan together and wondering why I wasn’t turning tan!

 

[lastresort]

hmm i might look into this with my doctor...

 

[CNCCurrency]

Yeah.. I was using gluta and melanotan together and wondering why I wasn’t turning tan!

Not in my experience using both, have been tanned for 6 months straight now since using mt 1 and gluta

 

[FlowerFairy]

Not in my experience using both, have been tanned for 6 months straight now since using mt 1 and gluta

I was taking glutathione 2000mg/day, 7 days a week. And I was on a conservative dose of mt1, only 5 days/wk. How much were you taking?

 

[chmuse]

I was taking glutathione 2000mg/day, 7 days a week. And I was on a conservative dose of mt1, only 5 days/wk. How much were you taking?

200 or 2000? My dosing might be WAY off 🤣

 

[CNCCurrency]

I was taking glutathione 2000mg/day, 7 days a week. And I was on a conservative dose of mt1, only 5 days/wk. How much were you taking?

That maybe why 2000mg a day! Most folks do 600 to 1200 mg a week split every other day.

 

[FlowerFairy]

That maybe why 2000mg a day! Most folks do 600 to 1200 mg a week split every other day.

Yep. That’s what I was thinking.

 

[FlowerFairy]

200 or 2000? My dosing might be WAY off 🤣

I upped it a lot for a while. I was getting sick if the wind blew and was trying to remedy that. I guess it worked- I haven’t been seriously sick in almost a year.

 

[chmuse]

I upped it a lot for a while. I was getting sick if the wind blew and was trying to remedy that. I guess it worked- I haven’t been seriously sick in almost a year.

I didn't know gluta helped with that!

 

[FlowerFairy]

I didn't know gluta helped with that!

That was one of the big reasons I started using gluta and nad+. I was getting sick constantly! Honestly didn’t know about the skin effects.