Weight-loss drugs fail: Users experience cravings comparable to heroin withdrawal

When Mercedes's doctor informed her in 2024 that she could be prescribed GLP-1 weight loss injections, she broke down emotionally. "When she said yes, I cried in her office. I didn't really stop crying for a week," she recalled.

"Finally, after being overweight my entire life, this was going to save me. My struggle, my burden, my shame was finally going to come to an end."

However, over time it was hope, not weight, that diminished.

"I was on Ozempic for nine months. Then I went on Wegovy for four months, then Contrave, and then Mounjaro for a few months. Nine months ago I started on Zepbound," Mercedes said. "Nothing has worked."

A recently retired teacher in her 50s, Mercedes represents a small proportion of people for whom these powerful weight-loss drugs, promoted by celebrities, prove ineffective.

Ozempic, a type 2 diabetes medication, and Wegovy, licensed for weight loss, both contain semaglutide, which mimics a naturally occurring hormone called GLP-1. These drugs slow stomach emptying, suppress appetite, and increase insulin production.

Mounjaro and Zepbound contain tirzepatide, which mimics both GLP-1 and another hormone, producing greater weight loss.

Clinical trials suggest these medications can help participants lose 15% to 20% of their body weight on average. Studies indicate potential benefits for heart problems, addictions, and fatty liver disease, with effects sometimes unrelated to weight loss.

Between 9% and a third of clinical trial participants lose less than 5% of their body weight, depending on the drug and dose. Researchers are now investigating why, hoping to tailor treatments and reduce side effects.

For Mercedes, non-response has been devastating. "Aside from not working and being so expensive, saying it's hard on self-esteem is a humongous understatement," she said. "It's been a real struggle with shame, regret, big bills, and disappointment that my body isn't working as it should."

Professor Alexander Miras, an obesity specialist at Ulster University, stressed that lack of efficacy cannot be blamed on patients. "If the drug doesn't reduce hunger and food intake for someone, it's just not going to work," he explained.

Mercedes tried strict lifestyle changes alongside medication but found the injections didn't suppress constant thoughts about food. "I'm going to die of obesity," she thought. "I was really strict for a month, but the cravings, which I can only compare to heroin withdrawal, were overwhelming. The food talk never ended."

She did lose 20 pounds that month, but not due to the medication.

Yury K, 57, also from Canada, tried multiple weight loss programmes before starting Wegovy. He exercises five days a week with kettlebells and avoids junk food. While his blood sugar and cholesterol improved and food noise decreased, his weight remained unchanged. "I started at about 242lb and after six months was still about 242lb," he reported. He also experienced constipation and sensitive skin.

Lucille, 53, based in Luxembourg, has taken GLP-1 medications for four years, initially for insulin resistance, starting with Saxenda before switching to Ozempic. Despite initial effectiveness, the medications no longer help her lose weight, even on Mounjaro at the highest dose. "It's as if nothing is having an effect any more," she said, noting the high cost and lack of insurance coverage.

The reasons for varying responses remain unclear. "The short answer to why some people don't respond is we don't really know," said Miras.

Research indicates motivation, intelligence, education, and socioeconomics don't predict response. However, age matters—older patients lose less. Sex plays a role—men lose less than women. People with type 2 diabetes also lose less weight than those without.

Studies suggest ancestry affects outcomes, with greater effectiveness in people of European ancestry and lesser effectiveness in those of African American ancestry.

Dr Mahesh Umapathysivam, an endocrinologist at Adelaide University, noted hormones may influence response. "There's growing evidence that oestrogen alters GLP-1 response. We see this in differences between sexes, and menstrual cycle timing affects response," he said. Menopausal hormone replacement therapy containing oestrogen is associated with greater weight loss in semaglutide users.

Genetics also matter. A recent study found a genetic variant affecting brain receptors where these drugs work. Adam Auton of 23andMe Research Institute explained carriers of one copy lost an extra 0.76kg on average, while those with two copies doubled that benefit—about 10% of expected weight loss.

Umapathysivam's team identified genetic variants affecting the PAM enzyme, which modifies hormones including GLP-1. People with these variants may show GLP-1 resistance, meaning standard doses produce reduced effects on weight, glucose, insulin, and gastric emptying.

Currently, predicting who will respond remains impossible.

Promising new drugs are in development. Miras suggested switching to Mysimba (the UK brand name for Contrave), a non-GLP-1 drug working similarly in the brain. It's not available through the NHS, only privately.

Weight-loss surgery may remain an option for non-responders. Miras noted that lack of response to GLP-1 drugs doesn't predict lack of response to bariatric surgery.

For those who lose little weight on these medications, Miras offered reassurance: "It's not your fault and it's not the drug's fault either. This is purely luck. I've seen it before—it's not very common, but it does happen."

Mercedes began treatment with high hopes. "There was so much publicity. So many people said 'Oh, I forgot to eat lunch' that I subconsciously ignored the possibility that the drugs might not work," she reflected.

"I wish I knew if there were others out there, like me, for whom these medications are just not effective at all."