A new study has linked semaglutide, the active drug ingredient in weight-loss and diabetic drugs like Wegovy and Ozempic, to suicidal ideation.

The finding “warrants urgent clarification,” the authors wrote.

Researchers analyzed the World Health Organization’s (WHO) database for adverse drug events. They compared the reporting rates of suicidal ideation and other suicidal behaviors from reports about semaglutide and another weight-loss drug of the same class, liraglutide (brand name Victoza and Saxenda). The reporting rates of suicidal ideation and other self-injurious behavior were then compared against all other drugs in the WHO database. The findings were also compared to other antidiabetic drugs like dapagliflozin, metformin, and orlistat.

The results, published on Wednesday in the JAMA Network Open, show that semaglutide was linked with a 45 percent greater likelihood of suicidal ideation when compared to other drugs. Liraglutide had no significant link to suicidality.

The authors noted a slight increase in adverse drug reports for both semaglutide and liraglutide up until August 2023. However, the rise was substantially more pronounced for semaglutide, climbing from 0 percent in 2017 to 0.8 percent in 2023, compared to liraglutide’s increase from 0.09 percent in 2014 to 0.4 percent in 2023.

Semaglutide was approved in 2017 while liraglutide was approved in 2011.

“Clinicians and patients should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as pharmacovigilance studies cannot prove that, but only show an association,” the study’s lead author Chiara Gastaldon, who is also a research fellow with the WHO, told The Epoch Times.

“What I take away from this is that there is increased reporting, we should be aware of this,” Dr. Roger McIntyre, professor of psychiatry and pharmacology at the University of Toronto, who was not involved in the study, told The Epoch Times in an email. “The reporting of an elevated signal in a pharmacovigilance database cannot establish causation, it is association only,” he said.

“Most of the drugs that have been studied for the management of obesity are central nervous system drugs. And so there’s long been a concern about any psychiatric adverse events associated with those drugs, be it anxiety, insomnia, depression, any of these things,” Patrick O’Neil, a professor in psychiatry and behavioral sciences at the Medical University of South Carolina and was not involved in the study, told The Epoch Times.

A media spokesperson for Novo Nordisk, the manufacturer of Ozempic and Wegovy, told The Epoch Times that the U.S. Food and Drug Administration (FDA) and conclusions from a European Medicines Agency (EMA) analysis did not find an association between the drug and suicidality. The company said that the recent study has “several limitations, including missing data on medication dose and treatment duration, limited ability to adjust for preexisting suicidal ideation or suicidal depression and alcohol and substance misuse, as well as a high proportion of off-label use.”

“Novo Nordisk is continuously performing surveillance of the data from ongoing clinical trials and real-world use,” the spokesperson added.

Most Reports Linked to Off-Label Use

The authors evaluated over 36 million reports in the pharmacovigilance database. They identified 110 cases of suicidality among semaglutide users and 160 cases among liraglutide users.

Between the two drugs, around half of the suicidality cases occurred when people took the drug off label, the researchers said.

“The observed high proportion of cases due to possible off-label use and a recently published postmarketing signal of misuse or abuse call for urgent clarification of patient-related and drug-related risk factors,” the authors wrote.

Taking semaglutide with antidepressants or benzodiazepines, a drug often prescribed for anxiety, was associated with a 150 to 300 percent greater increase.

Gastaldon said that the higher reports of suicidality among those who took antidepressants and or benzodiazepines could be an indication of underlying diseases such as depression and anxiety. “We suggest that physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment.”

It is very difficult to study suicidality in obese patients given the bidirectional relationship between obesity and depression, O’Neil said. That is, people who are depressed are more likely to become obese, and people who are obese are more likely to develop depression.

Conflicting Findings

The study is one of many that have linked semaglutide drugs to suicidal ideation and other suicidal behaviors. There have also been studies that found semaglutide was linked to reduced suicidality, as well as studies that found no significant link between use of such drugs and suicidal behavior.

Both the U.S. Food and Drug Administration and the European Medical Agency have investigated the link between semaglutide and suicidality. Both investigations yielded inconclusive results, though the FDA’s investigation is still ongoing.

“Contradictory results in studies based on pharmacovigilance data are quite expected,” Drs. Francesco Salvo and Jean-Luc Faillie, who wrote an editorial accompanying the JAMA Network Open study, said. A disproportionate study, like the current study, tends to use a larger variety of methods and models than other studies, thus having a wider variety of results, they noted.

“Our study has the strength of being a real-world study, meaning that patients reporting these ADRs (adverse drug reports) are the real people taking these medications,” Gastaldon said.

“Other published disproportionality analyses of the EMA and FDA databases suggested a signal of suicidal adverse reactions reported for GLP-1 RAs. Our results extend previous analyses.”

“[There are] probably more studies not seeing a relationship than there are that find it. Does that mean we can rule [suicidality] out? No,” O’Neil said.

No Established Mechanism

There is currently no mechanism that can explain the difference in drug adverse event reporting rates between the two drugs, according to McIntyre.

Unlike rimonabant, an obesity drug that was pulled off the market due to early reports of suicidality, there was a possible clear mechanism for rimonabant explaining why some people may become suicidal. Rimonabant targeted the endocannabinoid receptors to reduce people’s appetite and drive for more food, which are the same receptors cannabis targets to cause psychoactive effects.

Studies in bariatric surgeries found that those who have depression or anxiety are at a greater risk of suicide and researchers have proposed that high expectations of bariatric surgery may contribute to mental distress, Gastaldon said.

“An alternative hypothesis may consider very rapid weight loss related to adjustment problems such as inability to eat as expected and ultimately exacerbated mental distress in highly vulnerable patients,” she added.

McIntyre previously commented that semaglutide and liraglutide, which have been shown to reduce food cravings in both animals and humans, should be linked to a decrease in impulsivity and therefore suicidality.

Update: The article was updated with statements from Novo Nordisk and Chiara Gastaldon, the study’s senior author.