High doses of Adderall, a commonly prescribed medication for attention deficit hyperactivity disorder (ADHD), are associated with a significantly elevated risk of psychosis or mania, according to a recent study by McLean Hospital, a Harvard affiliate. The research, published in the American Journal of Psychiatry, reveals that patients taking more than 40 milligrams of Adderall daily face a fivefold increased risk of experiencing a first-time episode of psychosis or mania. This finding underscores the importance of careful dose management and patient monitoring when prescribing stimulant medications.
Dose-Dependent Risk of Psychosis
The study, led by Dr. Lauren V. Moran, a pharmacoepidemiology researcher at McLean Hospital, analyzed electronic health records from Mass General Brigham patient encounters between 2005 and 2019. The focus was on individuals aged 16 to 35, a demographic known to be at higher risk for the onset of psychosis and schizophrenia. Researchers compared 1,374 patients presenting with first-episode psychosis or mania to 2,748 control patients hospitalized for other psychiatric conditions, such as depression or anxiety.
The analysis revealed a strong correlation between high-dose amphetamine use and the incidence of psychosis or mania. Specifically, the attributable risk percentage among those exposed to any prescription amphetamine was nearly 63 percent, and for high-dose amphetamine, it was 81 percent. This suggests that a substantial proportion of psychosis or mania cases in amphetamine users could be attributed to the high doses of the drug. "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 Dr. Moran.
Methylphenidate vs. Amphetamine
Interestingly, the study found no significant increase in psychosis risk with methylphenidate (Ritalin) use, a finding consistent with previous research. This difference may be related to the varying mechanisms of action and dopaminergic effects of these two stimulant classes. Amphetamines are known to release higher levels of dopamine, a neurotransmitter implicated in psychosis, potentially explaining the increased risk observed with Adderall.
Clinical Implications and Limitations
While the study does not establish causality, the researchers propose a plausible biological mechanism involving the release of dopamine. They also acknowledge limitations, including potential inconsistencies in electronic health record keeping and the study's focus on a psychiatric hospital population in the Boston area, which may limit generalizability. Despite these limitations, the findings have important clinical implications.
Dr. Moran emphasizes that the results should not cause undue alarm but should prompt extra caution when prescribing amphetamines, particularly to individuals with risk factors for psychosis or mania. "There’s limited evidence that prescription amphetamines are more effective in high doses," she noted. "Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania."
The study was funded by a grant from the National Institute of Mental Health (NIMH).
