The known unknowns about Ozempic, explained

If you track the news at all, you’ve probably heard of a revolutionary new weight-loss drug called Ozempic.

The very idea of a novel miracle weight-loss drug might provoke eye rolls because this is the kind of thing we’ve seen before. Often, it’s a drug like ephedra, which was all the rage in the ’90s and 2000s. Ephedra did help people lose weight, but it was eventually pulled from the shelves because of its links to heart attacks, strokes, and seizures.

Ozempic, however, appears to be different, not just pharmacologically but also in terms of its broader potential impact. I’m not a physician, obviously, and I’m not an expert on weight-loss drugs, but I wanted to learn more about what’s happening here and what makes Ozempic unique.

So I invited journalist Johann Hari on The Gray Area to talk about his new book, Magic Pill: The Extraordinary Benefits and Disturbing Risks of the New Weight-Loss Drugs. It’s an eye-opening read, to say the least, in part because Hari both experimented with Ozempic himself and spent an enormous amount of time talking to the researchers developing and studying these drugs.

Hari and I discuss what we know (and don’t know) about Ozempic and all the ways this drug could change our world. As always, there’s much more in the full podcast, so listen to and follow The Gray Area on Apple Podcasts, Spotify, Pandora, or wherever you find podcasts. New episodes drop every Monday.

This conversation has been edited for length and clarity.

We’ve seen “miracle” weight-loss drugs before. What makes Ozempic different?

Lots of things. So the first is that it works on a completely new mechanism. If you eat something now, your gut will produce a hormone called GLP-1, and we now know that’s part of your body’s natural signals telling you that you’ve had enough. But natural GLP-1 only stays in your system for a few minutes. What these drugs do is inject into you an artificial copy of GLP-1, but instead of lasting for a few minutes, it stays in your system for a whole week.

It has this bizarre effect, I’ll never forget the second day I took it to research it for the book. I was lying in bed. I woke up and I had this really strange sensation, and I couldn’t locate in my body what it was that I was feeling. And then I realized I wasn’t hungry.

I had woken up and I wasn’t hungry. I don’t remember that ever happening before. And I went to this diner near where I live and I ordered what I used to order every day, which was a huge brown roll with loads of chicken and mayo in it. I had like three or four mouthfuls and I couldn’t eat anymore. I felt full.

One of the things that’s different is we know that these drugs produce a feeling of satiety that lasts. The feeling of being full and having had enough. And we know that they produce sustained weight loss over a significant period of time.

How confident are we in some of these early results, which are admittedly pretty startling?

Well, there’s an extremely high level of confidence that it produces significant amounts of weight loss. There’s been hundreds of studies involving tens of thousands of people, and that’s just in its use for obesity. These drugs have also been used for diabetics and for other purposes, which gives us some insight into the safety risks around the drugs as well.

If we’re talking about this hormone that’s not just in your gut but also in your brain, does that mean that this drug could potentially be a general anti-addiction drug, a drug that bolsters your capacity for self-control as opposed to just a weight-loss drug?

Because this is a hormone that’s made in your gut, it was thought that these drugs primarily affect your gut, that they work by slowing down your gastric system. And that’s true, there is certainly an effect on your gut. But we also know that you have GLP-1 receptors, not just in your gut but in your brain.

If you give these drugs to rodents and then you cut open their brains, you see that the drug goes everywhere in their brain. And the neuroscientists I interviewed and the science they produced strongly suggest that these drugs work primarily by changing what you want, by changing your cravings and your desires.

There’s a huge debate about how that works, and it’s slightly disconcerting to interview the leading neuroscientists and say, “Okay, you’re saying this works primarily on my brain. What’s it doing to my brain?” And they all say a very erudite vision of, “Ah, we don’t really know.”

There’s also a huge debate about both negative and positive effects that may be happening. There’s a debate about whether it’s causing depression or even suicidal feelings in a minority of users.

What we know at the moment is we have a huge amount of unbelievably promising evidence in animals. I interviewed loads of scientists who’ve been doing experiments on this. For example, I talked to professor Elizabeth Jerlhag, who’s at the University of Gothenburg in Sweden.

What she does is get a load of rats, and they get them to drink loads of alcohol and get them used to it. And rats quite like getting drunk, they wobble around their little cages. And so they give rats alcohol for long periods of time until eventually their cage looks like a bar in downtown Vegas, and then they inject them in the nape of their neck with GLP-1 agonist, the active component in Ozempic and Wegovy.

What they find is a dramatic reduction in how much alcohol they consume. It’s usually about 50 percent, and we discover that they get less dopamine when they drink alcohol. They like it less. They crave it less. They’ll put in less effort to get it. It really does change the amount of alcohol they want to consume. Initially, it was thought, okay, well, that could just be that these drugs reduce your desire for calories. Obviously, alcohol has caloric content, maybe it’s just that.

So other scientists then experimented with drugs that don’t have any calories in them. For example, professor Patricia Grigson, who’s at Penn State University, got rats to use fentanyl and heroin heavily, gave them GLP-1 agonists, and found that they used significantly less. Dr. Gregg Stanwood, who’s at Florida State University, gave mice cocaine. When they gave them GLP-1 agonists, they discovered the mice used far less cocaine, again by around 50 percent.

We’ve got a lot of anecdotes, a lot of people I spoke to who started to take Ozempic and saw their addictions go away, but very little human evidence so far. What we do have is a little bit of a mixed picture. We know that these drugs reduce smoking, but only if you combine them with a nicotine patch. We know they reduce alcohol use, but only for people who aren’t heavy drinkers at the start. We’ll know a lot more in the next few years because there’s a huge number of trials going on.

So the basic causal mechanism here is that the drug deactivates the reward centers of the brain?

This is highly disputed. There are different theories about what it’s doing to the brain. And everyone who gave me a theory said, look, “At this point, it’s speculative. We don’t know.”

One theory is exactly what you’ve articulated. You have reward centers in your brain and everything you do that gives you pleasure, whether it’s having sex, eating food, meeting up with a friend, you do in part because it makes your reward centers hum. And one theory is that I’m eating more salad and less Big Mac because the Big Mac is significantly less rewarding to me. So the gap between the Big Mac and the salad is now much smaller.

Now, that theory obviously raises a whole series of concerns. If it’s dampening my reward system for Big Macs, how do we know it’s not dampening my reward system for writing my next book or having sex or whatever it might be? And, indeed, there has been a safety signal raised around depression and suicide in a small minority of people using these drugs.

But a different theory is that these drugs boost a different system in your brain. As professor Paul Kenny explained to me, who’s the head of neuroscience at Mount Sinai, in addition to a reward system in your brain, you’ve got something called your satiety system. Satiety is a really important concept for understanding how we got into the obesity crisis and how these drugs work. Your satiety is just your feeling that you’ve had enough and you don’t want anymore. Kenny argues that these drugs aren’t dialing down your reward system so much as dialing up your satiety system.

So what happens when you stop taking this drug?

We’ve got mixed evidence about this. There may be a minority of people who keep the weight off, but it seems that most people regain most of the weight pretty quickly after they stop taking it. So it’s not a holiday romance, it’s a lifelong marriage, or it’s like statins or blood pressure medication. It works as long as you take it, but when you stop taking it, it stops working.

Are there any other potential downsides that researchers are thinking about?

When you talk about the risks, a lot of the scientists say, absolutely rightly, “Actually, we’ve got quite a lot of evidence here on these drugs. Diabetics have been taking them for 18 years.” So they say, “Look, if they cause some horrific short-to-medium term effect, it would’ve shown up in the diabetics by now. If it made you grow horns, the diabetics would have horns.” And that’s a good point, and it should give us some sense of security.

But equally, some other scientists say that if we’re going to base our confidence on the fact that these drugs are safe for diabetics, then let’s really dig into the data around diabetics.

For example, there’s a brilliant French scientist called Jean-Luc Faillie, and what he looked at was a very large group of diabetics who use these drugs, and then he looked at a comparable group of diabetics who were very similar in every other way but didn’t use these drugs. One thing he and his colleagues calculated is that these drugs, if they’re right, increase your risk of thyroid cancer by between 50 to 75 percent.

That’s significant!

Yeah. As he said to me, it’s important to understand what that doesn’t mean. That doesn’t mean if you take the drug, you have a 50 to 75 percent chance of getting thyroid cancer. If that was the case, we’d be having bonfires of Ozempic all over the world. What it means is that if you take the drug — if he’s right, and this is highly disputed — whatever your thyroid cancer risk was at the start, that risk will increase by between 50 to 75 percent.

Now, other people say thyroid cancer is relatively rare. 1.2 percent of people get it in their life, and 82 percent of people survive. Nonetheless, I was extremely alarmed by that. Against that, lots of other scientists said to me, “Well, look, even if that’s right, you’ve got to compare it to what would happen to your cancer risk if you just remain obese.” And actually, I was stunned by the evidence about the cancer risk just from being obese. One of the biggest preventable causes of cancer in the United States and Britain is obesity.

At this point, would you say the biggest risk is that we simply don’t know what the long-term effects of this drug are yet?

It’s the biggest risk for me personally, because a lot of the risks don’t apply to me. I’m obviously not going to get pregnant. I’ve never had thyroid cancer in my family. I didn’t experience a loss of pleasure in food. The one that I’m most worried about, this is not for myself, but eating disorders in young women.

Prior to the pandemic, we already had historically high levels of eating disorders among American girls. There are, of course, some boys. And then, during the pandemic, it rose from the already historically high level. I am extremely worried about what happens when people who are determined to starve themselves get hold of an unprecedentedly powerful weapon to amputate your appetite. My biggest worry is that we will have an opioid-like death toll of young women who starve themselves to death using these drugs who would not have been able to without these drugs.

Now, there’s a lot we can do to prevent that. At the moment, you can get these drugs from a doctor on Zoom. Doctors on Zoom are not good at assessing your body mass index. These drugs should only be prescribed in person by doctors who have training in detecting eating disorders. That’s not perfect. There’s still holes in that system, but it would prevent a lot of this harm.

Listen to the rest of the conversation and be sure to follow The Gray Area on Apple Podcasts, Spotify, Pandora, or wherever you listen to podcasts.