High doses of ADHD medications are associated with a higher risk of psychosis

Taking high doses of ADHD medication is associated with a more than five times higher risk of developing psychosis or mania, according to a new study published Thursday in the American Journal of Psychiatry.

This study is one of the first to establish a link between increasing doses of these drugs – particularly amphetamines – and a greater likelihood of psychotic symptoms.

The medications include Adderall, Vyvanse, and generic amphetamines such as dextroamphetamine.

The link between amphetamines and psychosis is not new. Amphetamines increase dopamine levels in the brain. The neurotransmitter plays a number of roles in the body, including memory, motivation and mood, but it has also been linked to psychosis.

The drugs “can flood the brain with dopamine, and when you flood the brain with dopamine, it can potentially trigger 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 was not proven, however, was that higher doses increase the risk of psychosis, a phenomenon known as the “dose-response relationship.”

“That’s what this study delivers,” said Dr. Will Cronenwett, vice chair of clinical affairs in psychiatry at Northwestern Medicine.

“The United States is experiencing something of an amphetamine moment,” Cronenwett said. “The popularity and use of amphetamines is high and continues to rise.”

Stimulant use has skyrocketed in the U.S. in recent years, especially among adults. A study published this year in JAMA Psychiatry found that prescription rates for amphetamines for attention deficit hyperactivity disorder increased 30% between 2018 and 2022 among 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 manufacturer of Vyvanse, said: “Takeda believes it is important that patients take our medicines in accordance with U.S. Food and Drug Administration (FDA)-approved labeling guidelines and in consultation with their prescribing physician.”

Teva Pharmaceuticals, the maker of Adderall, did not respond to a request for comment.

High doses

Lead study author Dr. Lauren Moran, a psychiatrist and researcher at McLean Hospital, a teaching hospital of Mass General Brigham in Boston, said it is not uncommon for people to develop psychosis in connection with amphetamines.

“We've seen this a lot,” Moran said. “We see college students who come to us with no major psychiatric history and are prescribed stimulants suddenly develop psychosis.”

In the new study, Moran and her colleagues reviewed electronic health records from Mass General Brigham from 2005 to 2019, focusing on adolescents and adults ages 16 to 35 – the typical age range for the onset of psychosis or schizophrenia. They identified 1,374 cases of patients hospitalized with first episodes of psychosis or mania, compared with 2,748 patients hospitalized for other psychiatric conditions such as depression or anxiety.

They also examined whether patients had been prescribed stimulants in the past month and, if so, at what dosage.

Patients taking the highest doses—more than 40 milligrams of Adderall, 100 milligrams of Vyvanse, or 30 milligrams of dextroamphetamine—were 5.3 times more likely to develop psychosis than patients who did not take stimulants.

The middle dose – 20 to 40 mg of Adderall, 50 to 100 mg of Vyvanse or 15 to 30 mg of dextroamphetamine – was associated with a 3.5-fold 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.

Another ADHD medication, Ritalin, which is not an amphetamine, did not have an increased risk of psychosis.

According to Moran, an analysis of national health insurance claims data found that about 6 percent of patients taking amphetamines were prescribed the highest dose and about 22 percent were prescribed the medium dose.

Cronenwett said the risk of developing psychosis from amphetamine remains low, at about 1 in 1,000, but people taking high doses should be aware of the risks.

“I would counsel patients who have a personal or family history of serious mental illness, including bipolar disorder with mania or schizophrenia,” he said. “If these types of illnesses run in the family tree, these individuals should be very careful about how much and at what dosage they take of these medications.”

Ballon agreed.

“There may be people taking stimulants for whom they are not necessarily effective,” he said. “What ends up happening is that the doses are increased to achieve that level of effectiveness, thereby exposing people to that increased risk.”