Hey guys, I'm writing this up to share my interest and subsequent experience with setmelanotide.
Most appetite suppressants work through GCPRs that are subject to desensitization; mainly dopamine, glp, gip, and glucagon. Since the MC4R is also a GCPR I thought it would be subject to the same desensitization, with setmelanotide showing long term effects only because it was meant to be used in individuals with genetic abnormal signaling.
However, upon further research, I found that the appetite suppressant effects of the MC4R actually come from inhibition of the Kir7.1 channel. Notably, although this channel closes in response to the MC4R, it's closure is dependent on activation alone and is not altered by receptor desensitization. https://www.science.org/doi/10.1126/scisignal.aab2761
My experience:
Approved dosages for genetic obesity is 1-3mg. I found 3mg once per day to cause minor nausea but not really stop me from eating. I found my max dose to be 9mg per day. This is slightly under HEDs used in animal testing without genetic abnormalities. I have not tried any higher as I am barely able to hit protein targets as it is. At this dose it is very difficult to hit 2500 calories. I've lowered it to 6mg. At this time I also completely stopped using semaglutide and retatrutide, at which I was at the max weekly dose for both. I have yet to notice any tolerance after a month of usage at the same dose. Setmelanotide lacks the long half life that the incretins do which facilitates progressive accumulation, so if it did cause desensitization you'd likely notice it much sooner.
I found the appetite suppressant effects to be more similar to stimulants than incretin peptides. It is honestly not enjoyable at all as it mostly just feels like constant mild nausea, but I never felt like I had to vomit. The key is to find the dose that causes you to be disinterested in food while not causing significant nausea. It doesn't make you full quicker, rather it makes you more likely to not eat in the first place.
Side effects
- ~5 point increase in systolic bp.
- Reflux, not as bad as GLPs but still there.
- The first few times I had stomach pain, mildly sharp, that lasted for 5-10 minutes. This appears to be a known side effect.
- I felt very 'tight' in that I had a desire to stretch and yawn a lot, especially in the morning. This actually really sucked in the beginning but is completely gone now. My joints felt very brittle and it felt more difficult to open things. It didn't make me weaker when working out though- it was definitely all psychological. This was clearly from initial potent MC4R activation that is now desensitized.
Most alarmingly is that inhibition of the kir7.1 channel may be dangerous for the eyes. From everything I could find, I do not believe this receptor-channel interaction occurs in the RPE. Although both kir7.1 and the MC4R are present in the eye, they don't seem to be located in the same types of tissue. There has been zero cases reported for blindness in the extensive years of trials, but nevertheless it is listed as a potential side effect, as it has not been proven definitely that this interaction does not occur. Additionally an FDA panel concluded that it likely does not cause eye related issues.
What we can at least infer is that kir7.1 blockade should only be done through MC4R inhibition for the possibility that it is localized to the brain, and not through a direct channel blocker that would function systemically.
I did not notice much tanning, also likely because of rapid desensitization. MT2 always made my face extremely orange anyway so this is a plus for me. I did notice more moles however, similar to MT2. Your experience may be different if you use slowly ascending dosages instead.
Cost is not too bad if you use raws. I paid $180 for 1 gram.
When I do stop using I'll update with side effects of coming off, and also update if I do notice any tolerance develop.
Most appetite suppressants work through GCPRs that are subject to desensitization; mainly dopamine, glp, gip, and glucagon. Since the MC4R is also a GCPR I thought it would be subject to the same desensitization, with setmelanotide showing long term effects only because it was meant to be used in individuals with genetic abnormal signaling.
However, upon further research, I found that the appetite suppressant effects of the MC4R actually come from inhibition of the Kir7.1 channel. Notably, although this channel closes in response to the MC4R, it's closure is dependent on activation alone and is not altered by receptor desensitization. https://www.science.org/doi/10.1126/scisignal.aab2761
My experience:
Approved dosages for genetic obesity is 1-3mg. I found 3mg once per day to cause minor nausea but not really stop me from eating. I found my max dose to be 9mg per day. This is slightly under HEDs used in animal testing without genetic abnormalities. I have not tried any higher as I am barely able to hit protein targets as it is. At this dose it is very difficult to hit 2500 calories. I've lowered it to 6mg. At this time I also completely stopped using semaglutide and retatrutide, at which I was at the max weekly dose for both. I have yet to notice any tolerance after a month of usage at the same dose. Setmelanotide lacks the long half life that the incretins do which facilitates progressive accumulation, so if it did cause desensitization you'd likely notice it much sooner.
I found the appetite suppressant effects to be more similar to stimulants than incretin peptides. It is honestly not enjoyable at all as it mostly just feels like constant mild nausea, but I never felt like I had to vomit. The key is to find the dose that causes you to be disinterested in food while not causing significant nausea. It doesn't make you full quicker, rather it makes you more likely to not eat in the first place.
Side effects
- ~5 point increase in systolic bp.
- Reflux, not as bad as GLPs but still there.
- The first few times I had stomach pain, mildly sharp, that lasted for 5-10 minutes. This appears to be a known side effect.
- I felt very 'tight' in that I had a desire to stretch and yawn a lot, especially in the morning. This actually really sucked in the beginning but is completely gone now. My joints felt very brittle and it felt more difficult to open things. It didn't make me weaker when working out though- it was definitely all psychological. This was clearly from initial potent MC4R activation that is now desensitized.
Most alarmingly is that inhibition of the kir7.1 channel may be dangerous for the eyes. From everything I could find, I do not believe this receptor-channel interaction occurs in the RPE. Although both kir7.1 and the MC4R are present in the eye, they don't seem to be located in the same types of tissue. There has been zero cases reported for blindness in the extensive years of trials, but nevertheless it is listed as a potential side effect, as it has not been proven definitely that this interaction does not occur. Additionally an FDA panel concluded that it likely does not cause eye related issues.
What we can at least infer is that kir7.1 blockade should only be done through MC4R inhibition for the possibility that it is localized to the brain, and not through a direct channel blocker that would function systemically.
I did not notice much tanning, also likely because of rapid desensitization. MT2 always made my face extremely orange anyway so this is a plus for me. I did notice more moles however, similar to MT2. Your experience may be different if you use slowly ascending dosages instead.
Cost is not too bad if you use raws. I paid $180 for 1 gram.
When I do stop using I'll update with side effects of coming off, and also update if I do notice any tolerance develop.
