Keeping your good mood while taking GLP-1s could take some intentionality, experts say

Editor’s note: If you or someone you know is struggling with suicidal thoughts or mental health matters, please call the 988 Suicide & Crisis Lifeline by dialing 988 to connect with a trained counselor, or visit the 988 Lifeline website.

Can a popular medication used to change your body also be affecting your mood?

It’s a question that some users of semaglutide and tirzepatide injections, sold as Wegovy and Zepbound for weight loss, have been asking as they report increased feelings of anxiety, depression and suicidal ideation –– prompting an evaluation from the US Food and Drug Administration this year.

Semaglutide and tirzepatide are both glucagon-like peptide-1 receptor agonists or GLP-1 agonists. Although originally prescribed to treat type 2 diabetes (Ozempic and Mounjaro), semaglutide and tirzepatide are becoming more and more popular for weight loss.

A report published on September 3 in the journal JAMA Internal Medicine showed “no clinically meaningful differences” in mental health scores between people who were using semaglutide and those who were not, according to lead study author Dr. Thomas Wadden, researcher on obesity treatment and professor of psychology in psychiatry at the Perelman School of Medicine at the University of Pennsylvania. The FDA investigation has also not yet found evidence of increased risk of suicidal ideation.

But the interplay between the medication and mental health is complex, with many factors involved, said Dr. Davide Arillotta, a resident doctor in the department of neurosciences, psychology, drug research and child health at the University of Florence in Italy. He was not involved in the September study.

If you are noticing an effect on your mood while using a GLP-1 medication, here’s what might be at play.

Antidepressant effects

For some, using a GLP-1 medication might relieve some anxiety or depression symptoms, Arillotta said.

Receptors for GLP-1 are found in the pancreas, the gut and several regions of the brain involved in mood regulation, he said.

“They can affect the release and activity of neurotransmitters such as dopamine and serotonin, which play a crucial role in emotional well-being,” Arillotta added. “For these reasons, GLP-1 RAs are thought to have antidepressant effects.” Dopamine and serotonin are mood-enhancing chemicals that are often called the “feel-good” hormones.

Researchers have also suggested that because type 2 diabetes and depression can have some overlapping causes, GLP-1 drugs that improve diabetes markers could also improve mental health outcomes, said Dr. Peter Ueda, assistant professor and resident physician in endocrinology at the Karolinska Institutet and Centre for Diabetes in Stockholm, Sweden. He was not involved in Wadden’s study, but was a researcher on another study on GLP-1 drugs and suicidality risk also published on September 3 in JAMA Internal Medicine.

Blood sugar

If you feel like your mood takes a drop while you’re on GLP-1 medications, what and how much you’re eating or drinking might be to blame.

The medications improve glycemic control, or your body’s ability to regulate your blood sugar so that it doesn’t get too high, said Dr. Amira Guirguis, professor of pharmacy and MPharm program director at Swansea University in Wales.

But the changes in blood glucose levels could have an impact on mood.

“Extremes in blood sugar can impact mood,” said Tara Schmidt, lead dietitian at the Mayo Clinic Diet, an online weight loss program. “For example, someone who is experiencing hypoglycemia, or low blood sugar, may feel irritable or anxious. There is some thought that frequent highs and lows related to food intake may also initiate negative moods.”

Schmidt and Guirguis were not involved in Wadden’s study, but Guirguis and Arillotta have previously published research on the topic of GLP-1 medications and mental health with Dr. Giuseppe Floresta, assistant professor in the department of drug and health sciences at the University of Catania in Italy, and Dr. Fabrizio Schifano, a professor of clincial pharmacology and therapeutics at University of Hertfordshire in the United Kingdom.

In addition to changing blood sugar control, the medications can curb hunger levels. And if you aren’t getting enough nutrients because you aren’t hungry, that could adversely affect your health and well-being, Wadden said.

“Being undernourished can become a factor in low mood,” Schmidt said in an email. “This is most likely to impact someone on a GLP-1 who is not meeting their calorie and nutrient needs due to side effects or simply lack of hunger.”

A disrupted status quo

Many people anticipate feeling happier, more connected and more confident after changing their size and shape, but sometimes they find that the social and lifestyle changes come with difficulty.

While medication-supported weight loss can increase confidence in some, in others, the “sudden alteration” can worsen symptoms of body dysmorphic disorder, “resulting in increased anxiety, depression, and suicidal ideation,” Guirguis said in an email.

Body dysmorphic disorder, or body dysmorphia, is “characterized by excessive preoccupation with an imagined defect in physical appearance or markedly excessive concern with a slight physical anomaly,” according to the American Psychological Association.

And the compliments aren’t always unambiguously good, she said.

“The societal approval that often follows weight loss can generate pressure to sustain the new body size, potentially encouraging harmful practices like restrictive dieting, excessive exercise, or ongoing misuse of weight-loss drugs,” Guirguis added.

Whether consciously or not, the relationship with food and weight might have also been protective for some people ­­–– particularly those who have experienced trauma or abuse, Wadden said.

“Even though you want to lose weight, and you feel like you’re healthier … all of a sudden, you can start to feel vulnerable,” he added.

The social and lifestyle changes that come with the quick and dramatic weight loss that often accompanies GLP-1 medications may require other aspects of your life to change, such as your coping strategies or your relationships, Wadden said. And that can be overwhelming.

Before losing weight, your relationship with your partner, family and friends might have functioned in a comfortable status quo, he said.

“Now you’ve lost it,” Wadden added.

Studies have not definitively shown that taking GLP-1s puts people without a history of mental health concerns at greater risk, Wadden said. But life is difficult, he said.

“At any given time, somebody is going through a stressful time,” Wadden said. “They may be grieving a loss or a loved one, they may have lost their job, you may have people developing depression, but that seems to be equally experienced by people on the drugs versus placebo,” he said, referring to his September study.

How to protect your mood

As a weight-loss medication reduces your hunger levels, it may become helpful to take an intentional approach to meeting your calorie, nutrient and hydration needs, Schmidt said.

“You have to treat this like a schedule,” she said. “I’m going to have something for breakfast by 9 a.m., and four hours later, if I haven’t had anything, I’m going to have something else.”

Your blood sugar levels will fluctuate throughout the day, but to help them stay within a healthy range, Schmidt recommends “eating well-balanced meals, avoiding high-sugar ultra processed foods and beverages, and eating meals at regular intervals.”

Incorporating regular exercise and getting enough sleep can also mitigate potential negative effects of the medications, Wadden said.

For those who have existing problems with severe depression and suicidal ideation, it’s important to pay careful attention to changes in mood when starting any medication, including GLP-1 drugs, Ueda said.

You should also discuss your history of significant mental illnesses — including major depressive disorder, bipolar disorder or post-traumatic stress disorder — with your doctor before starting the medications, Wadden added.

But even those who don’t have such a history should be working closely with their health care team, he said. Discuss any mood changes with your practitioner, no matter how subtle they may seem.

“Don’t do it alone,” Wadden said. “Social media is a great support, a great source of wisdom, but at times, you also do need to check in with health professionals.”

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