Wed, Apr-24-24, 23:57
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Plan: Muscle Centric
Stats: 238/153/160
BF:
Progress: 109%
Location: UK
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I tried Ozempic and lost three stone. But was I at risk?
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I tried Ozempic and lost three stone. But was I at risk?
Johann Hari, who has struggled with his weight since childhood, took Ozempic and was delighted with the result. Then he talked to scientists about its possible impact on the brain and began to have second thoughts
When the financial analyst Emily Field was commissioned by Barclays to predict the likely economic implications of the new generation of weight-loss drugs, she came back with a startling answer: this will be comparable to the invention of the smartphone. For 40 years, people have been gaining weight, with a trebling in global obesity rates since 1975 — but that trend now looks likely to be slammed into reverse. These new drugs, working in a very different way to previous weight-loss drugs, cause remarkable levels of physical shrinking: for Ozempic and Wegovy, people lose on average 15 per cent of their body weight in a year, while for the newer drugs coming down the line, it’s a staggering 24 per cent. As these drugs become more widely available, we are going to see a rapid shrinking of large parts of the population. Financial analysts have advised airlines that they will need to spend less money on jet fuel, because the average passenger is going to weigh so much less.
When I first learnt about these drugs, I realised they were going to deeply challenge me — in complex ways. Ever since my late teens, my weight has seesawed between being slightly underweight and obese. I kept receiving wake-up calls about where I could be heading that never quite woke me up. For example, on the afternoon of Christmas Eve in 2009, I went to my local branch of KFC in east London. I gave my standard order — a bucket of grease and gristle so huge that I’m too embarrassed to list its contents here. The man behind the counter said, “Johann! We have something for you.” He walked off behind where they fry the chicken and returned with all the other staff who were working that day. Together, they handed me a massive Christmas card. I opened it. They had addressed it, “To our best customer,” and all written personal messages. My heart sank, because I thought, this isn’t even the fried chicken shop I come to the most.
Then, just as Ozempic came onto the market, I received two jolts. I realised that I was now older than my grandfather ever got to be. He died of a heart attack at 44, and many of the men in my family are prone to serious heart problems. Around the same time, I learnt that an old friend — one of the wittiest people I have ever known — had died in her forties of a heart attack that took place while choking on food. We had built our friendship on our love of junk food and laughing at our swelling weights. Those jokes now turned to dust in my mouth.
I could immediately see the appeal of a drug that interrupts your unhealthy relationship with food and seems to reset it. But I was also intensely conflicted. I felt like I had seen this film before: once every few decades, going right back to the Twenties, a miracle anti-obesity drug is announced and people start to hoover it up — only for some catastrophic side-effect to be discovered, leaving a trail of sickened people in its wake. When it comes to the body, can there really be such a thing as a (smaller) free lunch?
To investigate this, I spent a year taking these drugs and doing a deep dive into their effects all over the world, from the United States to Japan to Iceland, interviewing more than 100 of the leading experts and others affected by these drugs in different ways. Almost at once, I began to see their power. Two days after I first injected myself with Ozempic, I went to Camden Market to meet up with a friend. I have wandered through its food stalls, chowing down a multicultural range of junk, since I was a small kid. I walked through all my favourite venues, and I experienced something unprecedented: I didn’t want to eat any of it. In the weeks that followed, it felt like my appetite had been almost amputated.
Even more strikingly, my tastes changed. I wanted healthier food. My godsons wanted to go to McDonald’s, and when I didn’t order anything, they stared at me, agape, and asked if I had been replaced by an impostor. Over the next year, I lost three stone. I knew it was possible this was saving my life: people taking the drugs have a reduction in their risk of heart attack and stroke by 20 per cent, and this is just one of many remarkable health benefits that take place when you lose a large amount of weight. We know from studies of bariatric surgery patients — the best comparison group for the effects of these drugs — that following their operation, they are 60 per cent less likely to die of cancer and 92 per cent less likely to die of diabetes-related causes. There were other, more incidental benefits to my own weight loss — for example, as the drug’s effects kicked in and I shrank, my neighbour’s hot gardener hit on me.
These drugs are often described by the people using them as “magic” — but as I explored the science behind them with the people doing cutting-edge work on their effects, I realised there are three ways in which they could be thought of in this way. The first is in the sense that they could be a solution to this problem — one so swift and so simple that it seems almost miraculous. There were days when it felt like this, and I thought to myself, all my life I craved this crappy food and now a little jab once a week has taken it all away? The second is that they could turn out to be an illusion that, when you look closer, is not what it seems — a magic trick. Or they could be magic in a third sense. Think about the most famous stories about magic — Aladdin or Fantasia. You get your wish, but your wish unfolds in ways you could never have imagined and causes all kinds of chaos. I realised I needed to find out: what kind of magic are these drugs?
It was disconcerting to learn how much we don’t know. Startlingly little is known about their long-term effects or even how they work. We know a few things, for sure. When you eat something, after a while your pancreas produces a hormone named GLP-1 (glucagon-like peptide 1), which is part of your body’s natural signals saying, stop eating, you’ve had enough. But natural GLP-1 only stays in your system for a few minutes, and then it’s washed away. So Ozempic and Wegovy (the same drug, marketed under different names) inject you with an artificial copy of GLP-1 that stays in your system for a whole week. That’s why I felt so full, so fast.
At first, it was thought that since this is a gut hormone, the effects of these drugs are primarily on your gut. But now the picture is shifting. Interviewing leading neuroscientists and studying their research, I learnt that there are GLP-1 receptors in your brain too — and many scientists believe that these drugs are primarily affecting their users by changing how their brains function. It felt like a more intimate and more risky transformation. As I studied the science, I discovered there are 12 significant risks associated with these drugs, beyond the well-known side-effects of nausea and constipation. One of them may be connected to this tricky question of how the drugs work on our brains.
Six months after I started taking Ozempic, I noticed something. Every morning, when I woke up, I experienced two sensations at the same time. I felt that my body was shrinking. I could put my hands on my stomach and feel that, where I had been pot-bellied, I was now lean. But I also felt something else. My mood was strangely muted. I didn’t feel as excited for the day as I normally do. I don’t want to overstate this — I wasn’t depressed. I was, some of the time, emotionally dulled.
It certainly wasn’t an all-consuming feeling. I had moments of feeling really happy. But I felt that my mood was slightly lower than it had been before I started taking these drugs, and I was puzzled. Why would I feel like this, when I was getting what I wanted? It’s possible it was just a coincidence and other things in my life unrelated to the drugs were bringing me down. Was Ozempic having a negative effect on my state of mind?
A significant minority of people across the world taking these drugs were raising similar concerns. Most people are pleased by the results and seem to experience a boost to their mood and self-esteem, but some doctors have raised a “safety signal” expressing concern that these drugs may have caused suicidal feelings in a small number of their patients. My own feelings were muted rather than acutely distressing — but I wondered if my lowness of mood might be a very small nod in that direction, potentially driven by the same causes. It led me to begin to investigate one of the many unpredictable possible effects of this pharmacological revolution: the potential psychological effects of these drugs.
There are two broad ways of thinking about this question. The first is that the drugs affect your psychology and how you think about yourself, and this may make some people feel sharply worse. The second is that they have a physical effect on your brain. (Of course, it could be some mixture of both.) I started by investigating the psychology. Before I began writing my book, if you had asked me why I ate, I would have said, obviously, the main reason is to sustain my body. But then Ozempic stripped me down to the core physical function of eating, and it dawned on me how little of my relationship with food had been driven by this urge. Before Ozempic, I ate around 3,200 calories a day. Now, when I ate only to keep my body going, I got by on 1,800 calories. Those other calories, it’s clear, were doing something else.
About seven months after I started taking these drugs, I had a rough day. I was in Las Vegas, investigating the murder of somebody I knew and loved for a book I am working on. It was harrowing. On autopilot, I went to a branch of KFC, and ordered what I would have asked for a year before. I sat there with a bucket of chicken and a feeling of sadness I wanted to drown in saturated fats, and realised I couldn’t eat it. Colonel Sanders was staring down at me from the wall and it felt like he was asking, “What happened to my best customer?” I thought: you’re just going to have to feel your feelings.
Lots of people use food primarily to manage their emotions. When a group of scientists was investigating comfort eating, one person said, “Food is like a sedative to me. It knocks me out, almost like a drug. When I feel any little bit of sadness or anger, I eat. It’s almost like being fed as a baby. I will eat and eat until I can’t move.”
Nearly 31 per cent of women and 19 per cent of men say they respond to stress by eating in order to feel better. On the night Donald Trump was elected president in 2016, as the news of each state going into the red column came in, food orders on apps like Grubhub and Uber Eats massively surged. In some places, there was a 46 per cent upswing in people ordering pizza, a 79 per cent rise in people ordering cupcakes, and a 115 per cent increase in people ordering tacos.
Sitting in that branch of KFC on West Sahara Avenue in Las Vegas, I realised something sobering. It’s only when your eating habits are taken away from you that you understand the job they were doing for you all along.
This shouldn’t be surprising — because we can look at what happens in the only other circumstance where people lose dramatic amounts of weight as a result of a medical intervention. Dr Carel Le Roux, a metabolic medicine specialist at University College Dublin, who played a key role in developing the new weight-loss drugs, told me: “After bariatric surgery, we see an increase in suicide fourfold.” This remains low, and most patients are glad they had the surgery because of the huge health benefits — but it’s still a significant effect. A significant minority of bariatric surgery patients experience major depression: one study found 17 per cent suffered mental health problems so severe they required inpatient psychiatric care, and another long-term follow-up found 29 per cent experienced a major depressive episode.
Le Roux believes that for some patients, overeating has performed a psychological function, and afterwards there’s “this hole, this space, left in their reward areas that’s not filled any more”.
In addition, some people believe that losing weight will solve all their problems and set them free to become who they really want to be, but when they actually lose weight, many of them, he said, then realise, “I have the same job and I drive the same car and I live in the same house and I have the same partner. Actually, it wasn’t the disease of obesity that made my life terrible. It was all this other stuff.”
But there is another way of thinking about why these drugs could potentially be having this effect. In addition to having positive effects on your brain, could they also be having negative effects on it? Professor Robert Kushner, who was involved in the trials of Wegovy, told me, “If you do animal studies and you tag the compound… you look at where it goes in a rodent’s brain, it’s everywhere. It’s deep in the brain — in the appetite centre, in the reward centres and the homeostatic centres.” Dr Clemence Blouet, who is researching this question at Cambridge University, agreed, saying the receptors for these drugs are “in lots of different areas… It’s everywhere.”
It was disconcerting to realise that the scientists studying this don’t know much about how it is affecting the brain, only that it is having a profound effect there. Blouet went on, “Some people say the brain is the most complex object in the universe.” So it’s hardly surprising that when it comes to these drugs, “We’re still trying to understand how everything works.” But there are several different theories, which are all fairly speculative at the moment — but some of them may help to explain some of the unexpected psychological effects of these drugs.
One of these theories is that these drugs work by dialling down the “reward centres” of the brain. Professor Paul Kenny, who is the chairman of the school of neuroscience at Mount Sinai Hospital in New York, explained: “The reward centres are there to keep you alive… If you’re hungry and you eat food, the reason the food feels pleasurable is because you engage those pleasure centres in your brain.”
The same goes for when you have sex or connect with other people — all of these activities make your reward centres hum. “The role of those centres is to encourage you to approach, obtain and consume factors that are required for life and its propagation.” This, he said, is “absolutely crucial… If you don’t experience pleasure from the things that are important for sustaining, maintaining and propagating life, there’s a very good chance that you won’t engage in those types of behaviours.”
It’s possible that these drugs make you eat less, because when you take them, you find lousy food less rewarding. But for me, this begs an obvious question. If they dial down the rewards you get from eating, could they be dialling down the rewards you get from other activities too?
The first person to raise concerns about this with me was Dr Gregg Stanwood, a neuropharmacologist working on these drugs at Florida State University. He said that if this way of thinking about how the drugs work is right, then, over time, taking these drugs “might be experienced as anhedonia”. This is when you have a seriously reduced ability to experience pleasure — or, as he put it, “blunted reward”. He stressed he doesn’t think that is likely, “but I need to suggest that, theoretically, it’s possible”. When I asked Professor Patricia Grigson at Penn State University, who carried out groundbreaking work showing that GLP-1 agonists or mimics reduce the use of heroin and fentanyl in rats, about this, she said, “I think it’s a fundamental question.” She explained, “What I think is important to figure out is making sure people [taking these drugs] are still tending to their real needs with vigour.”
But she added that your reward system goes beyond just meeting your basic needs. “If you think about a triathlete or a marathon runner, or any of us who aspire to be the best at whatever we’re engaging in — a person who wants to be the best violinist. These things take thousands and thousands of hours of motivation and energy. Are we going to have that? Are we going to interfere with that? If we interfere with that, we’ll be in big trouble.” Anhedonia is “a possible scenario”, she said, and she is concerned.
There are other possible ways of thinking about the brain effects of these drugs, ones that make this prospect less likely. For example, some scientists, like Kenny, think that instead of dialling down the reward system, they dial up our “satiety systems” — the parts of your brain that tell you you’ve had enough.
I put these concerns about the drugs potentially causing depression to the companies that make them. Novo Nordisk, which makes Ozempic and Wegovy, said it “will continue to monitor reports of adverse drug reactions, including suicide and suicidal ideation, through routine pharmacovigilance and in cooperation with local health authorities”. It pointed out that because the drugs affect the nervous system, they carry a suicide warning in the US, and pointed to one study that suggested no increase in psychiatric disorders for these drugs after 39 months of exposure. Neither the United States Food and Drug Administration nor the European Medicines Agency has been persuaded by the evidence presented so far that these drugs may be linked to depression or suicide. Eli Lily, which makes the other weight loss drug in this class available in the UK, Mounjaro, declined to comment.
After several months of taking the drugs, I went to visit an old friend and told her I was thinking of quitting them, because of these effects. She put her hand on mine. “Johann, it’s not triggering these issues. These issues were there all along. It’s just bringing them into view.” She leant forward. “I don’t believe that Ozempic is the drug that caused this problem. I think it’s just reduced your ability to use the drug you were using to soothe yourself for so long — food. You can stop taking the Ozempic, sure. Stop if you want to. But these issues will still be driving you. Use this as an opportunity to figure out why you ate in the way you did and change it.”
She said try to imagine food not being about what you put in your mouth, but what you put into your central nervous system, what you put into your organs, what you put into your muscle tissue, what you put into your skin, what you put into your gut. Think of that as its destination — rather than your mouth and your emotions as the destination.
I realised that she was right. I continued to take these drugs — but I also began to explore with a therapist the complex reasons why I began to overeat when I was a child. Just as importantly, at the embarrassingly late age of my mid-forties, I learnt how to cook and how to dance. Slowly, I started trying to take pleasure in them, to learn not to judge my body for how it looked, but to appreciate it for what it can do and the joy it can give me. As I did, the negative psychological effects of taking these drugs have faded away.
I could not have predicted at the start that taking Ozempic would send me on this emotional journey. In a similar way, I don’t think that as a society we have begun to properly plan and assess where these drugs are going to take us — though we can begin to see significant hints.
In 2007, when Steve Jobs unveiled the first iPhone, nobody could have guessed the road it would send us all on — to Twitter, TikTok and Trump. Similarly, the new weight-loss drugs aren’t going to only affect our weights. They are going to reshape our psyches and our societies — in complex and unpredictable ways. Some are clearly disturbing: eating disorder experts are worried there will be reams of dead young girls when anorexics get hold of these drugs. Do the 12 risks associated with these drugs outweigh the risks of continuing to be obese? How do we deal with the underlying social factors that made so many of us obese in the first place, so our children and grandchildren don’t face this lousy choice between a risky medical condition and a risky drug?
But right now, every overweight person who can afford these medications is going to have to make a decision. Dr Shauna Levy, an obesity specialist at the Tulane School of Medicine, told me, “We don’t know the long-term side-effects,” of these new weight-loss drugs. “But we do know the long-term side-effects of living with obesity.” And they are grim.
Reluctantly, with a lot of doubt, I have chosen my set of risks. Now, while I continue to take them and periodically feel torn about what I am doing, I remember what Professor John Wilding — who leads research into obesity at the University of Liverpool and helped develop these drugs — said about weight loss. “Why should we make it really difficult for people? Are we just punishing them for being fat? I say we should make it easier for them. We will then improve health.”
Magic Pill: The Extraordinary Benefits and Disturbing Risks of the New Weight Loss Drugs by Johann Hari (Bloomsbury) is published on May 2.
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https://www.thetimes.co.uk/article/...stone-grsrv2fql |
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