On a recent episode of the Goop podcast with Gwyneth Paltrow, Stanford neuroscientist and podcaster Andrew Huberman spoke at length about GLP-1 receptor agonists, covering their origins, mechanisms, side effects, and the emerging third-generation d**g Retatrutide.
Huberman began by sharing a surprising piece of origin trivia about the discovery of GLP-1–based treatments, explaining that their roots trace back to research on reptiles rather than humans.
“That was discovered because a biologist was studying Gila monsters. Gila monsters don’t need to eat very often. Some nerdy biologist was like, hm, I wonder how they don’t get hungry, isolated a peptide from the Gila monster. Turns out that’s the GLP,” he said.
He then shifted to the limitations of earlier GLP-1 d**gs, particularly the unintended consequences that can occur without proper lifestyle support like resistance training.
“You get a lot of muscle loss unless people resistance train. For some people they get a lot of gastric discomfort because there are receptors in the hypothalamus that controls hunger and there are also receptors in the gut, so it makes people feel really full. And there are receptors for the GLPs all over the brain. Just like serotonin and SSRIs, it’s not a clean treatment. People get side effects. Same thing with the GLPs,” he said.
Huberman went on to explain how the field evolved from modest early formulations to the powerful modern medications that dramatically increase circulating hormone levels, referencing widely used d**gs like Ozempic and Mounjaro.
“The early versions of these d**gs existed a while ago where you could agonize, meaning increase the amount of GLP-1, and those were two to four-fold increases in GLP-1. People did not lose much weight if any. Then they developed Ozempic, Mounjaro, which increased levels of circulating GLPs like a thousandfold. The brain and body are not accustomed to seeing this. People would lose a ton of weight but they would also lose muscle mass. They would just go into subcaloric mode so fast, it would reduce appetite so fast at the level of the brain and the body,” he said.
Addressing the backlash from some in the exercise and fitness world, Huberman argued that obesity is not simply a matter of willpower, emphasizing the biological changes that occur once significant fat mass accumulates.
“People from the exercise community, I think unfairly, said hey listen, you just need to do lifestyle things. I do think that once a person puts on enough adipose tissue it changes the hormone environment, which changes the brain, and there’s a lot of dysregulation that makes it really hard for them to just eat less. I’m not trying to give people a pass. I do think that people should take really good care of themselves, but these d**ugs were saving lives,” he said.
Finally, Huberman discussed the emerging third-generation treatment retatrutide, describing how it works differently from earlier GLP-1 d**gs by targeting multiple metabolic pathways at once.
“Retatrutide is a more mild agonist of GLP-1. It also increases glucagon and something called GIP. So it hits three different pathways, each a bit more subtly. Lower side effect profile, and people lose up to a third of their body weight across a year or so. It does seem to have some muscle-sparing effect,” he said.
