New Study Shows High Doses of Amphetamine Increase Risk for Developing Psychosis

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A new study of adult emergency department admissions at Mass General Brigham, led by McLean Hospital researchers, found that individuals taking high doses of amphetamine—like Adderall—have a 5-fold increased risk for developing psychosis or mania.^1,2

According to investigators, individuals with past-month prescription amphetamine use had a greater likelihood of new-onset psychosis or mania than individuals without past-month use. The highest risk was seen in patients taking 30 mg or more of dextroamphetamine, which corresponds to approximately 40 mg of Adderall. While previous research linked stimulants to psychosis and mania risk, there was little information on whether dosing impacted risk. With prescribing rates for stimulants to treat attention-deficit/hyperactivity disorder (ADHD) at an all-time high, it is an important issue to note.

“New-onset psychosis or mania is a rare but serious side effect of prescription amphetamines. Currently, US Food and Drug Administration labels do not have recommended upper limits on doses for the most commonly prescribed mixed amphetamine salts (Adderall). Our study found that doses higher than 30 mg dextroamphetamine equivalents, which is 40 mg of the mixed amphetamine salts (eg, Adderall), are associated with a more than 5-fold increase in the risk of psychosis or mania,” Lauren Moran, MD, a pharmacoepidemiology researcher at McLean Hospital and a member of the Mass General Brigham health care system, shared with Psychiatric Times. “Caution should be exercised when using high dose amphetamines, and we recommend screening for symptoms of psychosis or mania when patients need high doses of prescription amphetamines.”

Investigators reviewed electronic health records of patient encounters at Mass General Brigham between 2005 and 2019, focusing on adults aged 16 to 35. All patients were admitted to McLean Hospital following referrals from other hospitals in the Mass General Brigham health care system. The researchers identified 1374 cases of individuals presenting with first-episode psychosis or mania, compared with 2748 control patients with 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, to isolate the effects of stimulants.

They found the attributable risk percentage among those exposed to any prescription amphetamine was nearly 63% and for high dose amphetamine was 81%. These findings suggest that among individuals who take prescription amphetamine, 81% of cases of psychosis or mania could have been eliminated if they were not prescribed 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. This is consistent with previous research.³ Limitations of the study include inconsistencies with how electronic health records are kept. Additionally, the findings may not be generalizable to the entire United states, as the research took place in a psychiatric hospital in the Boston area that sees many patients with psychosis.

Moran shared that the current study was born out of her observations and experiences as an inpatient psychiatrist.

“As a psychiatrist who treated patients on the schizophrenia and bipolar disorders inpatient unit at McLean Hospital, we were seeing patients admitted for new onset psychosis and/or mania in setting of prescription stimulant use, most commonly on high doses of prescription amphetamines,” Moran exclusively told Psychiatric Times. “I started doing research on this topic several years ago to raise awareness of this issue and determine what stimulant type was associated with higher risk. In previous work, we found that prescription amphetamine use was associated with a higher risk of psychosis than methylphenidate. The current work builds upon our prior work by finding a dose response effect.”

Moran has a few ideas as to amphetamine alternatives, which she shared with Psychiatric Times: “Alternative strategies include use of methylphenidate, which was not associated with an increased risk of psychosis or mania, or using non-stimulants such as atomoxetine or guanfacine. The totality of evidence in this study (across main and secondary analyses) does not suggest there is an increased risk of psychosis/mania in individuals taking <= 15 mg dextroamphetamine equivalents (equivalent to 20 mg of Adderall). Behavioral strategies in combination with stimulants can be helpful, for example, working with patients on developing better time management skills.”

While the current study does not prove causality, the investigators 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.

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.

“The risk of psychosis and mania is a rare side effect of stimulants, and there certainly are patients who may benefit from higher doses of amphetamine if they are still having significant impairment from ADHD symptoms. It is likely that individuals who have been on high doses for a long time without any significant side effects are at minimal risk. When using high dose amphetamines, I would recommend screening for symptoms of psychosis or mania. Having patients on high doses of amphetamines sign a release so you can talk to a family member could be helpful, as they can inform you of any concerning behaviors if they arise,” said Moran.

References

1. High doses of some prescription stimulants tied to increased psychosis risk. News release. September 12, 2024. https://medicalxpress.com/news/2024-09-high-doses-prescription-psychosis.html

2. Moran LV, Skinner JP, Shinn AK, et al. Risk of incident psychosis and mania with prescription amphetamines. Am J Psychiatry. Online ahead of print.

3. Moran LV, Ongur D, Hsu J, et al. Psychosis with methylphenidate or amphetamine in patients with ADHD. N Engl J Med. 2019;380(12):1128-1138.