Patients taking a high dose of a prescription amphetamine face more than a five-fold increased risk for developing psychosis or mania, according to research out of McLean Hospital, a Harvard affiliate.

Often prescribed to treat attention-deficit/hyperactivity disorder, the risk was highest in those taking 30 mg or more of dextroamphetamine (which corresponds to 40 mg of Adderall), according to the study. Findings were published Thursday in the American Journal of Psychiatry.

Previous studies have linked stimulants to psychosis and mania risk; however, information had been lacking on whether dosing impacted risk.

“Stimulant medications don’t have an upper dose limit on their labels, and our results show that it is clear that dose is a factor in psychosis risk and should be a chief consideration when prescribing stimulants,” said lead study author Lauren Moran, a pharmacoepidemiology researcher at McLean Hospital. “This is a rare but serious side effect that should be monitored by both patients and their doctors whenever these medications are prescribed.”

Moran said the study was born out of her past clinical observations as an inpatient psychiatrist. She and her McLean colleagues would regularly see patients coming in experiencing first episodes of psychosis, and their medical records would reveal they were prescribed high doses of stimulants by their doctors.

Researchers reviewed electronic health records of Mass General Brigham patient encounters between 2005 and 2019, focusing on adults aged 16 to 35, the typical age of onset for psychosis and schizophrenia. All patients were admitted to McLean Hospital following referrals from other hospitals in the Mass General Brigham healthcare system. The researchers identified 1,374 cases of individuals presenting with first-episode psychosis or mania, compared to 2,748 control patients with a psychiatric hospitalization for other conditions like depression or anxiety. They conducted a comparison analysis of stimulant use over the preceding month and accounted for other factors, including substance use, in order to isolate the effects of stimulants.

They found the attributable risk percentage among those exposed to any prescription amphetamine was nearly 63 percent and for high dose amphetamine was 81 percent. These findings suggest that among people who take prescription amphetamine, 81 percent of cases of psychosis or mania could have been eliminated if they were not on the high dose. While a significant dose-related risk increase was seen in patients taking high doses of amphetamine, no significant risk increase was seen with methylphenidate (Ritalin) use, which is consistent with previous research, including a 2019 study led by Moran.

While the study does not prove causality, the researchers note there is a plausible biological mechanism in neurobiological changes that include a release of higher levels of the neurotransmitter dopamine from amphetamines, that parallel dopaminergic changes observed in psychosis. 

Limitations of the study include inconsistencies with how electronic health records are kept. Additionally, with the research taking place in a psychiatric hospital in the Boston area that sees many patients with psychosis, it may make these findings less generalizable to other parts of the country.

Moran said the findings need not create alarm but should lead to extra caution when these medications are prescribed, especially for those who have risk factors for psychosis and mania.

“There’s limited evidence that prescription amphetamines are more effective in high doses,” said Moran. “Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania.”

This work was funded by a grant from the National Institute of Mental Health (NIMH), R01 MH122427.