High-dose amphetamine increases odds of psychosis, mania by fivefold

Key takeaways:

• A study author told Healio that psychosis is a “rare but serious” adverse effect of prescription stimulants.
• If possible, physicians should avoid prescribing dextroamphetamine doses greater than 30 mg.

Patients with past-month exposure to prescription amphetamines used to treat ADHD had higher odds of developing psychosis or mania compared with those without past-month exposure, according to a recent study.

Researchers reported in the American Journal of Psychiatry that the risk was greatest in patients who were prescribed more than 30 mg of dextroamphetamine equivalents. This corresponds to 40 mg of Adderall, according to a press release related to the study.

“The clinical implications are to make psychiatrists aware of this rare but serious side effect, avoid doses above 30 mg dextroamphetamine if possible, and include assessments for symptoms of psychosis or mania as part of their workflow when treating patients with ADHD with prescription amphetamines,” Lauren V. Moran, MD, MPH, a pharmacoepidemiology researcher at McLean Hospital, which is a member of the Mass General Brigham health care system, told Healio.

Previous reports have revealed a surge in ADHD diagnoses in recent years. Among adults in the United States, there was a fivefold increase in prescriptions for amphetamines between 2004 and 2019, “with a further increase of 11% to 19% in prescription stimulant use between 2020 and 2021, driven by amphetamines,” Moran and colleagues wrote. However, little is known about how the levels of stimulant doses impact the risk for psychosis or mania, they added.

Moran and colleagues conducted a case-control study at McLean Hospital to compare the odds of incident psychosis or mania in patients aged 16 to 35 years who used prescription amphetamine in the past month vs. those who did not.

The analysis included 1,374 case patients with new-onset psychosis or mania and 2,748 matched controls, all of whom were hospitalized between 2005 and 2019. The control group was comprised of patients who were hospitalized for a psychiatric condition other than psychosis or mania, most commonly anxiety or depression.

Overall, the researchers found increased odds for psychosis and mania among patients with past-month amphetamine use compared with no use (adjusted OR = 2.68; 95% CI, 1.9-3.77). They observed a dose-response association, with higher doses correlating with greater risks. Doses greater than 30 mg of dextroamphetamine equivalents were associated with 5.28-fold increased odds of psychosis or mania.

Moran and colleagues calculated attributable risk percentages, which they estimated to be about 63% among patients exposed to any prescription amphetamine and 81% among those exposed to high-dose amphetamine. This suggests that about 81% of psychosis or mania diagnoses in patients taking prescription amphetamine could have been avoided if the patients were not prescribed a high dose, according to the release.

In a secondary analysis evaluating past-month methylphenidate use, Moran and colleagues found no significant increase in odds of psychosis or mania compared with no methylphenidate use.

Moran said current literature indicates that methylphenidate is less effective in treating ADHD symptoms than prescription amphetamines, although the studies are short term and “generally do not include high dose amphetamines.”

When deciding which agent to prescribe patients with ADHD, Moran recommended starting with methylphenidate.

“Prescription amphetamines are more potent than methylphenidate, but we can look at treatment of pain as a comparison. In treating pain, we would not start with opioids, we would start with Tylenol or Advil and then use another agent if that didn’t work, and only use opiates when needed,” she said. “My personal opinion is to start with methylphenidate, and if that is ineffective, then switch to the more potent prescription amphetamines if symptoms of ADHD are not adequately controlled.”

However, for patients who have psychosis risk factors, Moran said to “avoid prescription amphetamines and use methylphenidate or nonstimulants that are approved for treating ADHD (eg, atomoxetine).”

Reference:

• High doses of some prescription stimulants tied to increased psychosis risk. https://www.eurekalert.org/news-releases/1057164. Published Sept. 12, 2024. Accessed Sept. 12, 2024.