Kathy Schwartz聽was 10 years free from alcohol, cigarettes and opiates but every day it was painful to control her cravings. 鈥淭hey were always in the background,鈥� 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. 鈥淚 do not crave, which I didn鈥檛 think would be a side effect,鈥� says Schwartz. Remarkably, the depression and anxiety that would previously come over her in waves also calmed down.
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Schwartz isn鈥檛 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 鈥� as well as neurological conditions such as 笔补谤办颈苍蝉辞苍鈥檚 disease and Alzheimer鈥檚. What鈥檚 more, it seems that these effects aren鈥檛 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 (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.
Semaglutide and more
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, , with the number of Americans taking GLP-1 drugs . Although a pill version called Rybelsus is available, these drugs are generally taken as weekly injections at home, typically helping people . 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 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 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. 鈥淲hen patients are responding, they feel more empowered,鈥� says at Albert Einstein College of Medicine in New York. 鈥淚t鈥檚 not simply the mood improvement, but a feeling that they have it under control 鈥� they feel good about themselves.鈥�
Mental health benefits
However, some researchers such as at the University of Toronto, Canada, think that additional mechanisms are at play. After all, GLP-1s aren鈥檛 only produced in the gut 鈥� they are also , 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 , and , 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 鈥淥n average, depressive symptoms improved by 30 per cent in the whole sample,鈥� says Mansur. These effects were observed even in individuals who didn鈥檛 lose a significant amount of weight, indicating that they weren鈥檛 simply due to feeling better through weight loss.
When the researchers carried out MRI scans of the participants鈥� brains, they found that in volume within a month. 鈥淲e were surprised by the magnitude,鈥� says Mansur, who is now the ability of GLP-1 drugs to directly treat mood disorders.
He suspects these brain effects are rooted in . For starters, this hormone has been shown to and to . 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鈥檚 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, and , independent of weight loss.
It is this anti-inflammatory effect that underlies GLP-1 drugs鈥� cardiovascular benefits, , as well as their such as 笔补谤办颈苍蝉辞苍鈥檚 and Alzheimer鈥檚 disease, which are both characterised by neuroinflammation. Clinical trials so far have had mixed results, but the latest findings for 笔补谤办颈苍蝉辞苍鈥檚, published in April, found that 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 had reduced shrinking in certain parts of their brains and less cognitive decline, compared with controls. A clearer picture of these drugs鈥� impact should emerge late next year, when pharmaceutical company Novo Nordisk completes testing semaglutide for Alzheimer鈥檚 disease.
Some researchers suspect these drugs will work against other brain conditions, such as epilepsy and stroke. 鈥淚t appears that the mechanisms that are protective in Alzheimer鈥檚 disease and 笔补谤办颈苍蝉辞苍鈥檚 disease also show effects in other neurodegenerative disorders,鈥� says at the Henan Academy of Innovations in Medical Science in China. 鈥淪ince 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.鈥�
In recent years, researchers have been taking advantage of this breadth to explore whether GLP-1s could treat addiction. For instance, in February, at Penn State Neuroscience Institute . 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.
Targetting addiction and cravings
While the exact mechanism is unclear, GLP-1s that are and : the nucleus accumbens and the locus coeruleus. The idea, according to animal studies and Grigson鈥檚 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.
鈥淭he same central nervous system effects that increase your satiety and reduce your cravings are also having other favourable effects,鈥� says at the Johns Hopkins School of Medicine in Maryland. 鈥淲e鈥檙e in a new era in terms of these agents that have so many benefits.鈥�
Indeed, beyond opiates, GLP-1s also seem useful for treating addictions to , 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 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, at the University of Oklahoma and his colleagues explored whether semaglutide could help people with , the most common type. Their than the only medication approved by the US Food and Drug Administration (FDA) for this condition. , another common eating disorder characterised by episodes of overeating then purging.
If confirm these findings, Richards believes GLP-1s could revolutionise mental healthcare 鈥� as part of a holistic treatment regimen involving dieticians, clinical psychologists and others. 鈥淚f we do find there is a reliable, say, binge eating response or alcohol use response, that鈥檚 going to make GLP-1s the most common medication with this effect by orders of magnitude,鈥� 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. and antipsychotics 20 to 45 kg, says Machineni, often forcing individuals to choose between their mental health or weight.
Some people will 鈥渁void coming to the psychiatrist, they avoid medication, they avoid things that would make their mental health better because they don鈥檛 want to end up with obesity鈥�, says , 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 鈥� a critical issue given .
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.
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 , but concluded in April that there was . A similar investigation by the FDA is ongoing, but a . Likewise, a 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鈥檛 yet know if people who aren鈥檛 overweight can take GLP-1s safely for mental health reasons alone. 鈥淭hese medications across the board reduce appetite,鈥� 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 , shortages or high costs, they might risk experiencing worse symptoms than before.
Adverse effects
Another, potentially stickier issue is GLP-1s鈥� cultural meaning, with some body positivity activists arguing that such drugs can damage mental health (these activists often prefer the term 鈥渇at鈥� over 鈥渙bese鈥�, which they argue is a term that pathologises larger bodies). 鈥淭his whole frenzy around Ozempic, Wegovy, has got a lot of people confused that this is a good thing for fat people,鈥� says author of Fierce Fatty and a consultant on anti-fat bias and diet culture. 鈥淚f they鈥檙e gonna make you thin, they鈥檙e gonna make you happy, they鈥檙e gonna end your depression 鈥� why wouldn鈥檛 I take it?鈥� What鈥檚 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.
a philosopher at Cornell University in New York, echoes these concerns. 鈥淎 lot of fat people report having intentional weight loss pushed on them by medical professionals,鈥� 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. 鈥淧eople who are bigger increasingly feel unwelcome in spaces where the question is, 鈥榃hy aren鈥檛 you on Ozempic?鈥� 鈥� says Manne. 鈥淭hat can have real effects on their mental health and sense of well-being.鈥�
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鈥檛 have excess weight or obesity, says Ndumele. Perhaps one day there will be a new formulation that doesn鈥檛 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. 鈥淛ust the way it鈥檚 helped my mental health and decision-making, I plan on taking it forever.鈥�
Simar Bajaj is a freelance writer and a research fellow at Massachusetts General Hospital
