In 1998 an asthma and allergy drug called montelukast hit the U.S. market under the name Singulair. In the years that followed, commercials filled with flowers and cats proclaimed that it was “a different way to treat allergies.” During the next two decades it became many doctors’ go-to antiallergy and asthma prescription—especially for children because, unlike other asthma medications, it comes in pill form and does not require fiddling with an inhaler. “It used to be prescribed like vitamins,” says Andrei Constantinescu, a pediatric pulmonologist at Columbia University Medical Center.
But for a few people, this dream medication turned out to be a nightmare. Some taking montelukast started to develop strange psychiatric symptoms. They became unusually irritable, and they experienced visual and auditory hallucinations, insomnia and even suicidal thoughts. This worrying pattern was especially prevalent in kids. In 2020 these reports prompted the Food and Drug Administration to issue Singulair and the generic versions of montelukast a serious label modification—a “black box” warning indicating severe or potentially fatal side effects.
Spurred by growing public awareness of these problems, scientists are now trying to figure out how widespread these side effects are—and how, exactly, an allergy drug is messing with people’s mind.
Montelukast belongs to a class of drugs known as leukotriene modifiers. These medications block leukotrienes—chemicals your body produces when it’s exposed to allergens—from binding to your cells. This stops the leukotrienes from triggering a cascade of unpleasant symptoms, including excessive mucus, coughing and tightness in your throat.
Montelukast remains one of the most widely used allergy and asthma treatments in the world. In 2021 an estimated 31 million people were prescribed some version of the drug in the U.S. alone.
What leukotriene modifiers such as Singulair are not supposed to do is cross the blood-brain barrier. But after the drug was approved, evidence started to mount that it was ending up in the brain. People taking montelukast wrote to the drug’s original manufacturer, Merck (Singulair is now made by the spin-off company Organon), to report that they or a family member experienced extreme agitation. Some developed insomnia or found themselves unable to sleep because of vivid, disturbing nightmares. Others became aggressive, anxious or even suicidal. Worse, the majority of people who experienced these symptoms were children.
“He would bang his head against the wall and I found kitchen knives under his pillow—thankfully only the butter knives he could access. All [of this occurred when he was] only three years old,” wrote one parent about their son’s experience on a generic version of montelukast in a series of public testimonials that were collected by the National Center for Toxicological Research. These reports helped prompt the FDA to issue its black box warning for the drug. In an e-mail to Scientific American, an FDA spokesperson said that the agency “continues to monitor and investigate this important issue and will [further] update the label if data support that changes are appropriate and necessary.”
The number and intense nature of these reports also raised alarm bells with researchers. “[It] makes you think that this should be studied a bit more carefully,” says Seena Fazel, a psychiatrist and director of the Center for Suicide Research at the University of Oxford.
Fazel teamed up with a group of forensic psychiatrists, pediatricians and public health experts that conducted its own study in 2022 in JAMA Network Open. After analyzing electronic health records from more than 72,000 people with asthma and nearly 82,500 people with allergies who were taking montelukast, the team found that the drug raised a person’s odds of being diagnosed with insomnia within a year of being prescribed montelukast by around 14 percent. And it upped one’s odds of being prescribed antidepressants by 16 to 17 percent. Fazel notes that the risk is relatively small on an individual level but is much more pronounced when applied to a large population. He also points out that more research is needed to suss out the full impact of the drug. “This is only, I think, a small piece of the jigsaw puzzle,” Fazel says. “But it’s an important piece.”
Scientists still aren’t sure exactly what montelukast does in the brain or even how it gets there. But new research is bringing them closer to unraveling these cryptic mechanisms. A recent study in mice suggests that montelukast alters levels of the brain chemicals dopamine and serotonin, which could affect mood. “We hypothesized that children may be more susceptible to [psychiatric] side effects due to the maturation stage of their brain,” says systems pharmacologist Cátia Marques, now at the University of Pennsylvania, who conducted the research. Montelukast might act in a similar way to other allergy drugs, such as corticosteroids, which readily cross the blood-brain barrier.
How did these side effects go unnoticed for so long? In retrospect, there were hints in some early rat studies that indicated that montelukast continued to build up in rodent brains some 24 hours after dosing. The results of rodent studies don’t always translate to human trials, however.
It is possible that researchers failed to notice the side effects in their original clinical investigations. Psychiatric symptoms tend to develop slowly, and they may wax and wane from day to day, Fazel says. The drug’s initial safety tests also focused more heavily on its acute physical health side effects because, at the time, the manufacturers assumed that its distribution to the brain was “minimal.”
But Merck’s 1996 original patent for Singulair mentioned that it might have additional uses in treating “cerebral spasm,” Reuters reported last June. Lawsuits filed against Merck cite this as evidence that the company knew montelukast had some significant brain impacts even before the drug received FDA approval. Merck did not immediately respond to a request for comment, though Organon, which now holds the Singulair patent, did.
“Nothing is more important to Organon than the safety of our medicines and the people who use them,” wrote a spokesperson for the company in an e-mailed statement to Scientific American. “We remain confident in the efficacy and safety profile of SINGULAIR when used in accordance with the FDA-approved Prescribing Information.”
As a practicing pediatrician, Constantinescu agrees that the FDA’s black box label offers sufficient warning to health care providers and patients. But he says it’s up to doctors to adequately convey the risks to the parents of children taking the drug.
By the time the FDA’s warning went out, Constantinescu had long since stopped prescribing montelukast to his patients. He had seen a handful of kids become irritable and depressed while taking the drug—although, luckily, not to the point of becoming suicidal. “Honestly, it wasn’t worth the effect,” especially because there are more effective medications available now, he says.
“We have better drugs for treating asthma,” he says. “So the prudent thing is to not use it unless you have good reasons.”
IF YOU NEED HELP
If you or someone you know is struggling or having thoughts of suicide, help is available. Call or text the 988 Suicide & Crisis Lifeline at 988 or use the online Lifeline Chat.