Does Semaglutide Raise the Risk Suicidal Thoughts?

The researchers of the latest study examined data from four out of five Semaglutide Treatment Effect in People with obesity (STEP) trials, and tracked changes in depression symptoms with the Patient Health Questionnaire-9 (PHQ-9).

They looked for indications of suicidal thoughts and behavior using the Columbia Suicide Severity Rating Scale and determined that suicide death among people using GLP-1 receptor agonists is rare.

While these findings may seem reassuring, however, the research may have some degree of bias.

Several study authors declared potential conflicts of interest because they are affiliated with Novo Nordisk, which produces semaglutide-containing drugs, or other drug manufacturing companies such as Eli Lilly, Sanofi, and AstraZeneca. The study also received funding from Novo Nordisk.

Still, another recent study published in Nature Medicine in January 2024 found no link between semaglutide use and suicidal ideation in a real-world cohort of 240,618 people with overweight or obestiy.

Similarly, other research on semaglutide use and suicidal ideation conducted in 2018 and 2021 found no association in people with obesity.

In addition, early trials of the GLP-1 agonist liraglutide (Saxenda) conducted in 2017 found that only 0.3% of those treated with liraglutide reported suicidal ideation compared with 0.1% of those taking the placebo. This difference was slight enough that the authors concluded there was “no cause for concern.”

Nonetheless, in July 2023, the European Medicines Agency (EMA) released a statement to explain they are “reviewing data on the risk of suicidal thoughts and thoughts of self-harm” associated with GLP-1 receptor agonists as researchers continue to debate over safety.

This review is ongoing, and both the Food and Drug Administration (FDA) and the British Medicines and Healthcare Products Regulatory Agency have since announced that they are conducting similar investigations.

So far, neither the FDA nor the EMA has found a cause for concern.

Much of the information about GLP-1 agonists and psychiatric symptoms stems from clinical trials.

However, people with psychiatric conditions are rarely included in clinical trials.

GLP-1 agonists have become wildly popular with millions of people using them, including those with mental health conditions. Understanding how this drug affects people in the real world is increasingly important.

In the JAMA Network Open study, the scientists analyzed global data from the World Health Organization (WHO).

They focused on the potential relationship between the GLP-1 agonists, liraglutide and semaglutide and suicidal ideation and self-harm.

The researchers used the WHO’s database of individual case safety reports (ICSRs).

The ICSR is the largest pharmacovigilance database in the world, containing more than 28 million reports of suspected adverse drug reactions from 140 countries.

“Pharmacovigilance is the science and activities involved in detecting, assessing, understanding, and preventing adverse effects or any other problems related to medicines,” explained study co-author Georgios Schoretsanitis, MD, PhD, a researcher with the Feinstein Institute for Medical Research.

“This ongoing process is essential for ensuring the safety of drugs even after they have been approved for public use,” Schoretsanitis told Healthline.

In this study, the scientists did find a relationship between semaglutide and suicidal ideation, but they did not find this relationship with other medications.

The authors also found evidence that “people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide.”

Although the JAMA Network Open results are concerning, it is important to put them into perspective.

For instance, the researchers used a method called disproportionality analysis to conduct their study. “In pharmacovigilance, researchers often compare ‘cases’ to ‘non-cases’ to understand if a drug might be associated with certain adverse events,” Schoretsanitis explained.

Cases are reports where people have experienced a particular adverse event after taking a drug, and non-cases are people who took the same drug but did not experience that adverse event.

“By comparing these groups, disproportionality analysis aims to detect unusual patterns in the data,” Schoretsanitis said, meaning there is a higher-than-expected number of adverse events happening with a particular drug.

If this “disproportionate” number of reports is greater than expected, this suggests that there is a “potential link between the drug and that adverse event that needs to be investigated further,” he added.

So, while this relationship certainly warrants a deeper dive, Schoretsanitis explained that the results are “like an early warning system, and should not be immediately viewed as an alarm.”

Still, Rachel Goldberg, an eating disorder therapy specialist in Studio City, CA, not involved in the study, urged caution.

“I believe we are still in the early stages of understanding how these drugs affect mental health, and establishing a clear correlation or cause-and-effect relationship will take more time,” she told Healthline.

“This study highlights that individuals on psychiatric medications who used GLP-1s tended to disproportionately experience suicidal ideation,” Goldberg continued. “This could suggest that GLP-1s may impact how psychiatric medications work, potentially reducing their effectiveness and leading to persistent thoughts that might not have occurred otherwise.”

Recent studies have found no links between semaglutide and suicidal ideation while others have shown the inverse. Why might this be?

“There is disagreement because the incidence is so rare that it is difficult to accurately assess and try to delineate a possible reason for this,” Mir Ali, MD, board-certified bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, told Healthline. Ali was not involved in the studies.

The authors of the JAMA Network Open study explain that previous research only included participants with obesity or diabetes. In contrast, the latest study also investigated people who took the drug “off-label.” In other words, their analysis included people without an obesity or diabetes diagnosis.

Sarah Boss MD, psychiatrist, psychotherapist, and clinical director at The Balance Rehab Clinic expressed similar concerns about off-label use of GLP-1 agonists. Boss was not involved in the studies.

“It is essential to understand that these medications are not first-line choices for people who do have type 2 diabetes, let alone people who do not,” she told Healthline.

“If these medications are used for physical or psychological purposes, it has the potential to damage people’s minds and bodies in serious ways. Type 2 diabetes is a metabolic disorder. If the drugs are used appropriately, that is different,” Boss continued.

“These medications can have a significant impact on our very delicate metabolic systems. If you disrupt the gut-brain connection, this can, of course, lead to mental health issues like depression, among other things.”

For anyone taking these drugs and experiencing suicidal ideation, Boss recommended “getting in touch with an internal medicine specialist to help wean them off the medication safely and detox to restore the body’s internal balance.”

A new study found no evidence of a link between the GLP-1 agonist semaglutide and suicide ideation, while another recent study showed the inverse. Although the relationship is not yet definitive, experts call for caution and more research exploring this potential link.