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GLP-1’s & Addiction

GLP-1’s & Addiction

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 Today we’re talking about peptides being researched for addiction. We’ll unpack the science behind the incretin system, how those pathways tie into reward and substance use, and focus in on the newest triple‐agonist retatrutide. We’ll also look at early evidence for alcohol, tobacco and other substance-use disorders when using certain peptide therapies. If you want to support what we do, head over to our Partners Page. You'll find some amazing brands we trust—and by checking them out, you're helping us keep the podcast going. https://pepties.com/partners/ What are GLP-1, GIP and the “dual/triple” agonists? First, let’s review some biology to ground the discussion. GLP-1 (glucagon‐like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are incretin hormones. Incretins are gut hormones that help with digestion and blood sugar control. They’re released by the gut in response to food. GLP-1 raises insulin levels after you eat to help lower blood sugar, slows gastric emptying, and reduces appetite. It also reduces how much glucagon your body makes. This helps to lower your blood sugar. Medications like semaglutide and dulaglutide work by mimicking GLP-1 and are often referred to as “GLP-1 agonists”. GIP has somewhat overlapping but distinct roles from GLP-1. It too, influences insulin secretion, but it also helps with fat metabolism. In a nut shell, GIP helps fat cells respond more efficiently to insulin so they release stored fat to be used as energy when your body needs it. This process helps your metabolism shift from just storing energy to burning fat for fuel. Medications like tirzepatide work by mimicking both GLP-1 and GIP and are often referred to as “dual” agonists. When GIP and GLP-1 are activated together — like in tirzepatide — they work as a team: GLP-1 helps control appetite and slow down digestion. GIP boosts how your body handles insulin and energy. Together, they help reduce hunger, improve metabolism, and burn fat more efficiently. Now here’s where it gets a bit tricky. A newer medication that’s still in development, retatrutide, works on three hormone pathways: GLP-1, GIP, and glucagon receptors. It’s called a “triple agonist”, and even though it activates the glucagon receptor, it doesn’t cause high blood sugar like you might expect. It’s about balance. In type 2 diabetes and obesity, the body’s hormone signals are out of balance. Retatrutide gently activates the glucagon receptor, but at the same time it strongly activates GLP-1 and GIP receptors — which still help control blood sugar and increase insulin. So blood sugar stays stable or even improves overall. Glucagon doesn’t just affect blood sugar — it also increases metabolism and helps the body burn fat and calories. By slightly stimulating glucagon receptors, retatrutide can boost energy use and promote fat loss without causing big spikes in blood sugar. As a result, you get the blood sugar control of GLP-1 and GIP, plus the fat-burning benefits of glucagon activation — leading to even greater weight loss and metabolic improvement. Right now, retatrutide is in phase 3 clinical trials, which are the final stage of testing before approval. These studies are expected to finish in early 2026, and if results look good, the FDA could approve retatrutide as early as 2027. Addiction Why is this relevant for addiction? Because the gut-brain axis, reward circuitry, and the pathways that regulate “wanting/consuming” food overlap with those involved in substance use. Appetite, reward, and craving may share neural substrates (dopamine, GABA, mesolimbic system) and so a drug that reduces drive to eat might also modulate drive to drink, smoke or use other substances. The link between GLP-1/related drugs and substance use disorders Let’s now dive into what the research says about GLP-1 receptor agonists (and related medications) in the context of alcohol, tobacco, and other substances. Let’s start with what we know from animal research. In pre-clinical studies, scientists have found that GLP-1 receptor agonists seem to change how animals respond to addictive substances. A systematic review showed that in rodents, treatment with GLP-1 drugs reduced the behavioral effects of alcohol, nicotine, amphetamine, and cocaine. For example, one GLP-1 drug called exendin-4 reduced alcohol-related behaviors in rodents. And even more recently, a study in both male and female rats showed that giving semaglutide, tirzepatide, or even retatrutide, reduced alcohol discrimination, meaning the rats didn’t experience the same “feeling” from alcohol as before. This means that the “interoceptive stimulus effects” or the internal sensations — how alcohol feels inside the body, changed. This is really important because this is what often drives people to drink or relapse. So, if these medications can blunt those internal cues, it suggests they might ...
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