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.

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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 disrupt the rewarding effects of alcohol that help maintain addiction.

When we shift to human studies, things get even more interesting. A systemic review found that out of five studies looking at GLP-1 receptor agonists in people with substance use disorders — mostly alcohol and nicotine — three showed real reductions in substance use, while two did not.

In one large observational study of over 150 adults with obesity who drank alcohol, those who were taking semaglutide or tirzepatide for at least 30 days reported fewer drinks, fewer binge episodes, and lower overall intake compared to people not on those drugs.

A phase 2 clinical trial of once-weekly semaglutide in adults with alcohol use disorder showed similar results — lower alcohol craving and some reductions in drinking behavior.

There’s also data from a massive registry-based study showing that people with alcohol or opioid use disorder who were prescribed GLP-1 or GIP drugs had 50% lower rates of alcohol intoxication and a 40% lower rate of opioid overdose.

Still, experts are cautious — meta-analyses and reviews consistently note that the evidence, while promising, is still early and we don’t yet have large, long-term randomized controlled trials.

What’s Going On?

So, what’s actually happening inside the brain and body that could explain these changes in craving and reward? How can medications originally made for diabetes and/or weight loss end up helping with addiction?”

Mechanistically, GLP-1 drugs may affect the brain’s reward system — especially dopamine signaling in areas like the nucleus accumbens — and reduce the “wanting” of reward substances like food or alcohol. They might also calm stress responses and make relapse cues less powerful.

And there are probably some physical effects too — things like slower digestion and increased fullness, which might make it harder to physically consume large amounts of alcohol or even smoke as much. But again, many of these findings come from animal models, which don’t always perfectly reflect human addiction.

Most of the focus so far has been on alcohol, though there’s also some early evidence that GLP-1 drugs might influence nicotine use. For substances like opioids or cocaine, the data is thinner and more mixed.

Bottom line — at this stage, GLP-1 receptor agonists, and maybe even GIP/GLP-1 dual agonists, represent a really promising new direction for treating addiction — but it’s still early days. We also don’t yet have human addiction studies on retatrutide, pre-clinical data in rats show that, like semaglutide and tirzepatide, it too, reduces alcohol discrimination.

In practical terms, if you’re treating patients with obesity or diabetes who also struggle with alcohol or nicotine use, choosing a GLP-1 or dual agonist might offer an unexpected bonus — helping with cravings.

It also gives us a new way to talk with patients about how metabolism, reward, and craving are all interconnected.

But — and this is important — the data are still limited. Most studies are small, short, and often focus on people with obesity or metabolic disease rather than pure addiction. So, for now, it’s an adjunctive idea, not a replacement for established therapies.

We’ll need larger randomized trials in people with substance use disorders to really understand who benefits, what doses work, and how long the effects last.

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Until next time, be well, and as always, have a happy, healthy week.

GLP-1’s & Addiction

The Peptide Podcast