Taking a high dose of ADHD drugs is linked to more than five times greater risk of developing psychosis or mania, according to a new study published Thursday in the American Journal of Psychiatry.
The research is among the first to find a relationship between escalating doses of the drugs — amphetamines, in particular — and a greater likelihood of psychotic symptoms.
The drugs include Adderall, Vyvanse and generic amphetamines, such as dextroamphetamine.
The link between amphetamines and psychosis isn’t new. Amphetamines increase levels of dopamine in the brain. The neurotransmitter plays a number of roles in the body, including in memory, motivation and mood, but it’s also implicated in psychosis.
The drugs “can flood the brain with dopamine, and when you flood the brain with dopamine you potentially can cause psychosis,” said Dr. Jacob Ballon, a psychiatrist and co-director of the INSPIRE Clinic at Stanford Medicine, a clinic specializing in patients with psychosis.
What hadn’t been established was that the risk of psychosis rose with higher doses, a phenomenon known as a “dose-response relationship.”
“That’s what this study provides,” said Dr. Will Cronenwett, vice chair for clinical affairs in psychiatry at Northwestern Medicine.
“The United States is having sort of an amphetamine moment right now,” Cronenwett said. “The popularity and use of amphetamines is high and getting higher.”
Stimulant use in the U.S. has skyrocketed in recent years, particularly among adults. A study published this year in JAMA Psychiatry found that prescription rates for amphetamines for attention-deficit hyperactivity disorder had risen 30% from 2018 to 2022 in people ages 20 to 39. Among people ages 40 to 59, rates rose 17%.
In a statement to NBC News, a spokesperson for Takeda Pharmaceuticals, the maker of Vyvanse, said, “Takeda believes it is important for patients to take our medicines in accordance with U.S. Food and Drug Administration (FDA)-approved labeling guidance and in consultation with their prescribing health care provider.”
Teva Pharmaceuticals, the maker of Adderall, didn’t respond to a request for comment.
High doses
The lead study author, Dr. Lauren Moran, a psychiatrist and researcher at McLean Hospital, a teaching hospital that is a part of Mass General Brigham in Boston, said it’s not uncommon for people to develop psychosis related to amphetamines.
“We’ve seen this a lot,” Moran said. “We are seeing college students coming in being prescribed stimulants who didn’t have much of a psychiatric history developing new onset psychosis.”
In the new study, Moran and her colleagues reviewed electronic health records from Mass General Brigham from 2005 through 2019, focusing on teens and adults ages 16 to 35 — the typical age range for the onset of psychosis or schizophrenia. They identified 1,374 cases of patients who were hospitalized with first episodes of psychosis or mania, compared with 2,748 patients who were hospitalized for other psychiatric conditions, such as depression or anxiety.
They also looked at whether the patients had been prescribed stimulants in the past month and, if so, at what dosages.
Patients taking the highest dosages — more than 40 milligrams of Adderall, 100 mg of Vyvanse or 30 mg of dextroamphetamine — were 5.3 times more likely to develop psychosis than patients taking no stimulants.
The medium dosage — 20 mg to 40 mg of Adderall, 50 mg to 100 mg of Vyvanse or 15 mg to 30 mg of dextroamphetamine — was linked to a 3.5 times higher risk. It’s not clear whether taking less than 20 mg of Adderall, 50 mg of Vyvanse or 15 mg of dextroamphetamine is associated with an increased risk of psychosis, Moran said.
There was no increased risk of psychosis with another ADHD drug, Ritalin, which isn’t an amphetamine.
Moran said that, according to an analysis of national insurance claim data, about 6% of patients taking amphetamines are prescribed the highest dosages and about 22% are prescribed the medium dosages.
Cronenwett said the risk of developing psychosis from an amphetamine remains rare, around 1 in 1,000. Still, people taking high doses should be aware of the risks.
“I would counsel patients who have a personal or family psychiatric history of serious mental illness, including things like bipolar disorder with mania or schizophrenia,” he said. “If these sorts of illnesses are in the family tree, then that’s somebody who might want to be very careful about how much of these medicines they use and in what doses.”
Ballon agreed.
“There may be some folks out there who are receiving stimulants for whom they’re not necessarily that effective,” he said. “What ends up happening is the doses get escalated to seek that level of effectiveness and in so doing put people at this increased level of risk.”
