Ozempic on the Brain
Weight-loss drugs have surprising benefits away from the gut, opening up new ways to treat depression, dementia and addiction, discovers Simar Bajaj.
KATHY SCHWARTZ was 10 years free from alcohol, cigarettes and opiates but every day it was painful to control her cravings. “They were always in the background,” she says. In June last year, however, this noise fell silent.
Prescribed the weight-loss drug semaglutide, she not only lost nearly 30 kilograms over 10 months, but also her desire to reach for a drink or take some pills. “I do not crave, which I didn’t think would be a side effect,” says Schwartz. Remarkably, the depression and anxiety that would previously come over her in waves also calmed down.
Schwartz isn’t alone in this experience. New research is revealing the surprising brain and mental health benefits of semaglutide drugs such as Ozempic and Wegovy, and other related diabetes and weight-loss drugs that mimic a gut hormone released after eating.
It is early days, but there are hints that these drugs could be repurposed to treat depression, anxiety, addiction and even certain eating disorders – as well as neurological conditions such as Parkinson’s disease and Alzheimer’s. What’s more, it seems that these effects aren’t just mediated via weight loss, but through direct action on the brain.
The story of drugs like Ozempic starts back in the 1970s and 1980s when researchers discovered that a gut hormone called glucagon-like peptide-1 (GLP-1) could stimulate insulin production when injected into rodents in the lab. More surprisingly, these animals started eating less and losing weight. We now know that the hormone leads to an increased feeling of fullness.
Today, drugs that mimic GLP-1, such as semaglutide (sold as Ozempic and Wegovy), liraglutide (sold as Saxenda and Victoza) and tirzepatide (which also contains another satiety hormone mimic, and is sold as Mounjaro and Zepbound), have revolutionised the treatment of diabetes and obesity. Already, 6 million people in the US have been prescribed semaglutide, with the number of Americans taking GLP-1 drugs predicted to grow to 30 million by the end of the decade. Although a pill version called Rybelsus is available, these drugs are generally taken as weekly injections at home, typically helping people lose around 15 to 21 per cent of body weight. These drugs can also protect against cardiovascular problems such as heart attacks. But their widespread use has revealed all kinds of other, unexpected knock-on benefits.
In February, an analysis of more than 4 million people by medical records company Epic found that most GLP-1 medications resulted in a lower likelihood of depression and anxiety compared with controls. For instance, people without diabetes taking semaglutide were 37 per cent less likely to be diagnosed with depression, and 31 per cent less likely to be diagnosed with anxiety. Similarly, a 2023 meta-analysis found that GLP-1 drugs reduced depression in adults with diabetes compared with those on non GLP-1 treatments.
Improved blood sugar control or weight loss might explain these mental health benefits, not least because there is a well-established link between obesity and depression. There is also a boost in confidence that may arise from addressing these conditions. “When patients are responding, they feel more empowered,” says Sriram Machineni at Albert Einstein College of Medicine in New York. “It’s not simply the mood improvement, but a feeling that they have it under control – they feel good about themselves.”
However, some researchers such as Rodrigo Mansur at the University of Toronto, Canada, think that additional mechanisms are at play. After all, GLP-1s aren’t only produced in the gut – they are also made in the brain, specifically the brainstem region. And, in turn, GLP-1 receptors are peppered throughout the brain, including in areas important for cognitive functions and emotional control, such as the prefrontal cortex, hippocampus and amygdala, so stimulating these receptors could be beneficial.
To test for broader effects, Mansur and his colleagues ran a small study in 2017, giving liraglutide to 19 people with major depressive disorder or bipolar disorder. Within a month, they reported better mood, attention span and cognitive function. “On average, depressive symptoms improved by 30 per cent in the whole sample,” says Mansur. These effects were observed even in individuals who didn’t lose a significant amount of weight, indicating that they weren’t simply due to feeling better through weight loss.
When the researchers carried out MRI scans of the participants’ brains, they found that areas involved in planning, organisation and emotional processing significantly increased in volume within a month. “We were surprised by the magnitude,” says Mansur, who is now conducting a randomised controlled trial to investigate the ability of GLP-1 drugs to directly treat mood disorders.
He suspects these brain effects are rooted in GLP-1’s multifaceted ability to protect the brain. For starters, this hormone has been shown to increase the brain’s blood flow and to slow down the death of nerve cells. It can also promote the flow of glucose to the brain, an incredibly sugar-hungry organ. Some studies in humans show that GLP-1 modulates the transport of glucose across the blood-brain barrier and the rate that the brain consumes glucose, says Mansur, increasing access to this vital energy source and hence, presumably, boosting the brain’s ability to operate.
But insufficient glucose is only one of many threats to the brain. Others include oxidative stress, where unstable molecules called free radicals damage neurons, and long‑term inflammation, where an overzealous immune system attacks healthy nerve cells. By binding to receptors in the brain, GLP-1 seems to reduce production of free radicals and dampen inflammation, independent of weight loss.
It is this anti-inflammatory effect that underlies GLP-1 drugs’ cardiovascular benefits, reducing the risk of heart attacks, as well as their promise for treating neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, which are both characterised by neuroinflammation. Clinical trials so far have had mixed results, but the latest findings for Parkinson’s, published in April, found that disease progression was reduced in participants treated with an older GLP-1 drug called lixisenatide, compared with controls. In tests of motor scores after 12 months, those receiving the drug had stayed roughly the same, whereas the control group had declined.
Similarly, last year a UK trial found that people with Alzheimer’s who were treated with liraglutide had reduced shrinking in certain parts of their brains and less cognitive decline, compared with controls. A clearer picture of these drugs’ impact should emerge late next year, when pharmaceutical company Novo Nordisk completes two trials testing semaglutide for Alzheimer’s disease.
Brain protection
Some researchers suspect these drugs will work against other brain conditions, such as epilepsy and stroke. “It appears that the mechanisms that are protective in Alzheimer’s disease and Parkinson’s disease also show effects in other neurodegenerative disorders,” says Christian Hölscher at the Henan Academy of Innovations in Medical Science in China. “Since the GLP-1 action in the brain is quite broad and does not focus on a specific biomarker of a specific disease, it is easy to see that the changes induced by GLP-1 type drugs are helpful in other diseases as well.”
In recent years, researchers have been taking advantage of this breadth to explore whether GLP-1s could treat addiction. For instance, in February, Patricia Sue Grigson at Penn State Neuroscience Institute presented the first clinical trial results using anti-obesity drugs to treat opioid addiction. Among 20 patients in residential treatment, those on liraglutide had a 40 per cent reduction in opioid cravings over three weeks compared with those receiving a placebo. Grigson and her colleagues are now conducting a larger trial to investigate further.
While the exact mechanism is unclear, GLP-1s seem to target addiction similarly to how they target the hunger drive, influencing two key brain regions that are involved with reward processing and cravings: the nucleus accumbens and the locus coeruleus. The idea, according to animal studies and Grigson’s unpublished data, is that GLP-1s reduce activity in both regions, simultaneously reducing the pleasurable aspects of taking opiates and the negative aspects of going through withdrawal.
“The same central nervous system effects that increase your satiety and reduce your cravings are also having other favourable effects,” says Chiadi Ndumele at the Johns Hopkins School of Medicine in Maryland. “We’re in a new era in terms of these agents that have so many benefits.”
Indeed, beyond opiates, GLP-1s also seem useful for treating addictions to nicotine, cocaine and other drugs. The strongest evidence yet for this came last month in a study of the medical records of over 80,000 people with obesity. This found that semaglutide was associated with around a 50 per cent lower incidence of alcohol use disorder over a 12-month follow-up period, compared with controls who were taking non GLP-1 obesity medications.
Compulsive behaviours are also associated with certain eating disorders, so last year, Jesse Richards at the University of Oklahoma and his colleagues explored whether semaglutide could help people with binge eating disorder, the most common type. Their study of 98 people’s medical records found that semaglutide was more effective at treating binge eating disorder than the only medication approved by the US Food and Drug Administration (FDA) for this condition. Other evidence suggests that GLP-1s might also help treat bulimia nervosa, another common eating disorder characterised by episodes of overeating then purging.
If ongoing trials confirm these findings, Richards believes GLP-1s could revolutionise mental healthcare – as part of a holistic treatment regimen involving dieticians, clinical psychologists and others. “If we do find there is a reliable, say, binge eating response or alcohol use response, that’s going to make GLP-1s the most common medication with this effect by orders of magnitude,” says Richards.
Beyond all of this, there is a very practical way that GLP-1 drugs can improve mental health: by tackling a major side effect of many psychiatric drugs, weight gain. Antidepressants can cause people to gain 10 to 20 kilograms and antipsychotics 20 to 45 kg, says Machineni, often forcing individuals to choose between their mental health or weight.
Some people will “avoid coming to the psychiatrist, they avoid medication, they avoid things that would make their mental health better because they don’t want to end up with obesity”, says Tiffani Bell Washington, a Boston-based psychiatrist and obesity medicine physician. Indeed, a number of US psychiatrists consulted for this article reported that, with GLP-1s increasingly available, people have become more willing to try and ultimately stay on psychiatric medication – a critical issue given high non-adherence rates.
Yet many questions remain. The key clinical trials testing semaglutide and tirzepatide for weight loss mostly excluded people with depression, anxiety and other mental health conditions, says Machineni. That has left a major gap in the research, making it unclear what mental health side effects these higher-risk individuals might experience.
Adverse effects?
This situation came to a head last year following reports of people on GLP-1s experiencing suicidal thoughts. In July 2023, the European Medicines Agency started an investigation, butconcluded in April that there was no link between these medicines and suicidal ideation. A similar investigation by the FDA is ongoing, but a preliminary evaluation in January found no causal link. Likewise, a recent observational study of nearly 2 million people found that GLP-1s were actually associated with a lower risk of suicidal ideation than other obesity and diabetes treatments.
Some experts are also concerned that people with anorexia may use GLP-1s and exacerbate their condition, or that otherwise healthy people might develop this eating disorder, characterised by extreme caloric restriction and an intense fear of gaining weight. We also don’t yet know if people who aren’t overweight can take GLP-1s safely for mental health reasons alone. “These medications across the board reduce appetite,” says Machineni, potentially leading patients without obesity to become malnourished or even critically underweight. And if people stop taking GLP-1 medications, whether due to side effects, shortages or high costs, they might risk experiencing worse symptoms than before.
Another, potentially stickier issue is GLP-1s’ cultural meaning, with some body positivity activists arguing that such drugs can damage mental health (these activists often prefer the term “fat” over “obese”, which they argue is a term that pathologises larger bodies). “This whole frenzy around Ozempic, Wegovy, has got a lot of people confused that this is a good thing for fat people,” says Vinny Welsby, author of Fierce Fatty and a consultant on anti‑fat bias and diet culture. “If they’re gonna make you thin, they’re gonna make you happy, they’re gonna end your depression – why wouldn’t I take it?” What’s missing in these rosy depictions is that these drugs may only be a band-aid, masking much deeper problems of weight-based discrimination and a socially disconnected society, says Welsby.
Kate Manne, a philosopher at Cornell University in New York, echoes these concerns. “A lot of fat people report having intentional weight loss pushed on them by medical professionals,” she says, even if they feel comfortable with their bodies. She worries that GLP-1 drugs will only exacerbate this situation, especially given their constant promotion by influencers, celebrities and the media. “People who are bigger increasingly feel unwelcome in spaces where the question is, ‘Why aren’t you on Ozempic?’ ” says Manne. “That can have real effects on their mental health and sense of well-being.”
Notwithstanding these issues, using GLP-1 drugs as everyday mental health treatments will require further research into their exact mechanisms of action, the feasibility of using low doses and their tolerability in people who don’t have excess weight or obesity, says Ndumele. Perhaps one day there will be a new formulation that doesn’t result in so much weight loss, but preserves the independent benefits to mental health and more.
But Kathy Schwartz has already made up her mind on semaglutide. “Just the way it’s helped my mental health and decision-making, I plan on taking it forever.”
Source: NewScientist, Apple News
