That can have an unexpected consequence, according to a new study that found adults taking high doses of amphetamine, such as Adderall, face more than a five-fold increased risk for developing psychosis or mania.
The new study of adult emergency department admissions at Mass General Brigham, led by McLean Hospital researchers, was published in the American Journal of Psychiatry.
The researchers determined that adults with past-month prescription amphetamine use had a greater likelihood of new-onset psychosis or mania than adults without past-month use. The study advised that the risk was highest in those taking 30 mg or more of dextroamphetamine, which corresponds to 40 mg of Adderall.
While previous studies linked stimulants to a greater risk of psychosis and mania, it had not been clear whether dosing was a factor.
“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, MD, 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.”
The case-control study used electronic health records to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients aged 16 to 35 years hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety.
Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use.
The results indicated that the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio, 2.68; 95% CI, 1.90-3.77) among 1,374 case subjects and 2,748 control subjects.
“A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania,” the authors wrote. “Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio = 0.91, 95% CI = 0.54–1.55).”
The researchers said that their results “suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.”
Dr. Moran said that she and her McLean colleagues would routinely see patients coming in experiencing first episodes of psychosis, and their medical records would reveal that they had been prescribed high doses of stimulants.
For the study, the team reviewed electronic health records of Mass General Brigham patient encounters between 2005 and 2019, focusing on adults aged 16 to 35 years, the typical age of onset for psychosis and schizophrenia.
The study found the attributable risk percentage among those exposed to any prescription amphetamine was nearly 63% and for high-dose amphetamine was 81%. That means that among patients who take prescription amphetamine, 81% of cases of psychosis or mania could have been eliminated if they were not on the high dose, according to the authors. 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.
No causality was proven by the study, but the researchers explained that there is a plausible biological mechanism in neurobiological changes that include a release of higher levels of the neurotransmitter dopamine from amphetamines, paralleling dopaminergic changes observed in psychosis.
“There’s limited evidence that prescription amphetamines are more effective in high doses,” Dr. Moran stated. “Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania.”
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