The first RCT for GLP-1 drugs and alcoholism isn't what we hoped

or what people seem to think

dynomight.net/glp-1

GLP-1 drugs are a miracle for diabetes and obesity. There are rumors that they might also be a miracle for addiction to alcohol, drugs, nicotine, and gambling. That would be good. We like miracles. But we just got the first good trial and—despite what you might have heard—it’s not very encouraging.

Semaglutide—aka Wegovy / Ozempic—is a GLP-1 agonist. This means it binds to the same receptors the glucagon-like peptide-1 hormone normally binds to. Similar drugs include dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide. These were originally investigated for diabetes, on the theory that GLP-1 increases insulin and thus decreases blood sugar. But GLP-1 seems to have lots of other effects, like preventing glucose from entering the bloodstream, slowing digestion, and making you feel full longer. It was found to cause sharp decreases in body mass, which is why supposedly 12% of Americans had tried one of these drugs by mid 2024.

(I’m skeptical that of that 12% number, but a different survey in late 2024 found that 10% of Americans were currently taking one of these drugs. I know Americans take more drugs than anyone on the planet, but still…)

Anyway, there are vast reports from people taking these drugs that they help with various addictions. Many people report stopping drinking or smoking without even trying. This is plausible enough. We don’t know which of the many effects of these drugs is really helping with obesity. Maybe it’s not the effects on blood sugar that matter, but these drugs have some kind of generalized “anti-addiction” effect on the brain? Or maybe screwing around with blood sugar changes willpower? Or maybe when people get thinner, that changes how the brain works? Who knows.

Beyond anecdotes, are some observational studies and animal experiments suggesting they might help with addiction (OKeefe et al. 2024). We are so desperate for data that some researchers have even resorted to computing statistics based on what people say on reddit.

So while it seems plausible these drugs might help with other addictions, there’s limited data and no clear story for why this should happen biologically. This makes the first RCT, which came out last week, very interesting.

This paper contains this figure, about which everyone is going crazy:

I admit this looks good. This is indeed a figure in which the orange bar is higher than the blue bar. However:

1. This figure does not mean what you think it means. Despite the label, this isn’t actually the amount of alcohol people consumed. What’s shown is the result of a regression, which was calculated on a non-random subset of subjects.

2. There are other figures. Why isn’t anyone talking about the other figures?

What they did

This trial gathered 48 participants. They selected them according to the DSM-5 definition of “alcohol use disorder” which happens to be more than 14 drinks per week for men and 7 drinks per week for women, plus at least 2 heavy drinking episodes. Perhaps because of this lower threshold, 34 of the subjects were women.

The trial lasted 9 weeks. During it, half of the subjects were given weekly placebo injections. The other half were given weekly injections of increasing amounts of semaglutide: 0.25 mg for 4 weeks, then 0.5 mg for 4 weeks, and then 0.5 or 1 mg in the last week, depending on a doctor’s judgement.

Outcome 1: Drinking

The first outcome was to simply ask people to record how much they drank in daily life. Here are the results:

If I understand correctly, at some point 6 out of the 24 subjects in the placebo group stopped providing these records, and 3 out of 24 in the semaglutide group. I believe the above shows the data for whatever subset of people were still cooperating on each week. It’s not clear to me what bias this might produce.

When I first saw that figure, I thought it looked good. The lines are going down, and the semaglutide line is lower. But then I checked the appendix. (Protip: Always check the appendix.) This contains the same data, but stratified by if people were obese or not:

Now it looks like semaglutide isn’t doing anything. It’s just that among the non-obese, the semaglutide group happened to start at a lower baseline.

How to reconcile this with the earlier figure? Well, if you look carefully, it doesn’t really show any benefit to semaglutide either. There’s a difference in the two curves, but it was there from the beginning. Over time, there’s no difference in the difference, which is what we’d expect to see if semaglutide was helping.

The paper provides other measurements like “changes in drinking days” and “changes in heavy drinking days” and “changes in drinks per drinking day”, but it’s the same story: Either no benefit or no difference.

So… This is a small sample. It only lasted nine weeks, and subjects spent many of them on pretty small doses. But this is far the miracle we hoped for. Some effect might be hiding in the noise, but what these results most look like is zero effect.

Outcome 2: Delayed drinking

There are also lab experiments. They did these at both the start and end of the study. In the first experiment, they basically set each subject’s favorite alcoholic drink in front of them and said them, “For each minute you wait before drinking this, we will pay you, up to a maximum of 50 minutes.”

How much were they paid, you ask? Oddly, that’s not specified in the paper. It’s also not specified in the supplemental information. It’s also not specified in the 289 page application they made to the FDA to be able to do this study. (Good times!) But there is a citation for a different paper in which people were paid $0.24/minute, decreasing by $0.01 / minute every five minutes. If they used the same amounts here, then the maximum subjects could earn was $9.75.

Anyway, here are the results:

So… basically nothing? Because almost everyone waited the full 50 minutes? And they did this for only $9.75? Seems weird.

I don’t really see this as evidence against semaglutide. Rather, I think this didn’t end up proving much in either direction.

Outcome 3: Laboratory drinking

So what’s with that initial figure? Well, after the delayed drinking experiment was over, the subjects were given 2 hours to drink as much as they wanted, up to some kind of safe limit. This is what led to the figure everyone is so excited about:

When I first saw this, I too thought it looked good. I thought it looked so good that I started writing this post, eager to share the good news. But at some point I read the caption more carefully and my Spidey sense started tingling.

There’s two issues here. First of all, subjects were free to skip this part of the experiment, and a lot did. Only 12 of the 24 subjects in the placebo group and 13 of 24 in the semaglutide group actually did it. This means the results are non-randomized.

I mean, the people who declined to do this experiment would probably have drunk different amounts than those who agreed, right? So if semaglutide had any influence on people decision to participate (e.g. because it changed their relationship with alcohol, which is the hypothesis of this research) then the results would be biased. That bias could potentially go in either direction. But basically this means we’re sort of working with observational data.

The second issue is that what’s being show in this plot is not data. I know it looks like data, but what’s shown are numbers derived from regression coefficients. In the appendix, you can find this table:

Basically, they fit a regression to predict how much people drank in this experiment at the end of the study (“g-EtOH”) based on (a) how much they drank during the same experiment at the start of the study (“Baseline”) (b) their sex, and (c) if they got semaglutide or not (“Condition”). Those coefficients are in the B column.

How exactly they got from these coefficients to the numbers in the figure isn’t entirely clear to me. But using a plot digitizer I found that the figure shows ~56.9 g for the placebo group and ~33.3 g for the semaglutide group, for a difference of ~23.6 g. I believe that difference comes from the regression coefficient for “Condition” (-25.32) plus some adjustments for the fact that sex and baseline consumption vary a bit between the two groups.

So… that’s not nothing! This is some evidence in favor of semaglutide being helpful. But it’s still basically just a regression coefficient computed on a non-randomized sample. Which is sad, since the point of RCTs is to avoid resorting to regression coefficients on non-randomized samples. Thus, I put much more faith in outcome #1.

Discussion

To summarize, the most reliable outcome of this paper was how much people reported drinking in daily life. No effect was observed there. The laboratory experiment suggests some effect, but the evidence is much weaker. When you combine the two, the results of this paper are quite bad, at least relative to my (high) hopes.

Obviously, just because the results are disappointing does not mean the research was bad. The measure of science is the importance of the questions, not what the answers happen to be. It’s unfortunate that a non-randomized sample participated in the final drinking experiment, but what were they supposed to do, force them? This experiment involved giving a synthetic hormone and an addictive substance with people with a use disorder. If you have any doubts about the amount of work necessary to bring that to reality, I strongly encourage you to look at the FDA application.

OK, fine, I admit that I do feel this paper “hides the bodies” slightly too effectively, in a way that could mislead people who aren’t experts or that don’t read the paper carefully. I think I’m on firm ground with that complaint, since in the discussions I’ve seen, 100% of people were in fact misled. But I’m sympathetic to the reality that most reviewers don’t share my enlightened views about judging science, and that a hypothetical paper written with my level of skepticism would never be published.

(People think the problem with science is that it’s too woke. While I don’t really disagree, I still think the bigger problem is screwed up incentives that force everyone oversell everything, because that’s what you have to do to survive. But that’s a story for another time.)

Anyway, despite these results, I’m still hopeful that GLP-1 drugs might help with addiction. This is a relatively small study, and it only lasted 9 weeks. I don’t think we can dismiss the huge number of anecdotes yet. And the laboratory experiment was at least a little promising. Given how destructive addictions can be, I vote for more research in this direction. Fortunately, given the billions of dollars to be made, that’s sure to happen.

But given just how miraculous semaglutide is for obesity, and given the miraculous anecdotes, I don’t see how to spin this paper as anything but a letdown. It provides weak evidence for any effect and comes close to excluding the possibility of another miracle. If you’ve forgotten what miracles look like, here is the figure for body weight: