Amphetamines
Loren Bonner
Dose appears to play a role in the event of a psychotic episode for patients prescribed amphetamines for ADHD, according to research published in the October 2024 issue of the American Journal of Psychiatry.
A psychotic episode is a rare but serious adverse outcome. Researchers observed that high doses of amphetamine—40 mg or higher—were associated with a roughly fivefold increased odds of psychosis or mania for patients aged 16 to 35 years who were hospitalized at McLean Hospital in Massachusetts for incident psychosis or mania between 2005 and 2019.
“I was not surprised by the authors’ conclusion but was surprised by the high doses of dextroamphetamine equivalents,” said Sandy Mitchell, PharmD, BCPP, a clinical pharmacy specialist in child and adolescent psychiatry who was not involved with the research.
“The maximum daily recommended dose for mixed amphetamine salts is 40 mg and lisdexamfetamine is 100 mg,” said Mitchell, who is also clinical assistance professor at the VCU School of Pharmacy. “It would have been interesting to see the mean doses of all stimulants and frequency of prescribing between the groups.”
Researchers relied on observational data, using EHRs to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines.
Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use.
Lead author Lauren Moran, MD, MPH, said the results can provide some practical advice to clinicians to be on the lookout for high doses of such prescriptions.
“Maybe there should be some questions of ‘why above 40 mg of Adderall?’ and also patients being more closely monitored,” said Moran.
Amphetamine prescribing has increased in the United States in recent years. According to CDC, the percentage of adolescent and adults receiving prescription stimulant fills grew during 2016 to 2021, particularly from 2020 to 2021. During the pandemic, telehealth made access to ADHD medications much easier, too.
Given that the risk of psychosis and mania with amphetamines appears dose-related, using the lowest effective dose is warranted, said Charles Caley, PharmD, BCPP, from the College of Pharmacy and Health Sciences at Western New England University in Massachusetts.
“The pharmacy practice implications should be for monitoring patients for behavior changes when they are treated with high-dose—or increasing doses—of amphetamine treatments in adolescent and adult patients, especially when they have psychiatric comorbidities and are treated with concurrent psychiatric pharmacotherapy,” said Caley.
Amphetamines vs. methylphenidate
Moran said the study expands upon her prior research from 2019 that found a higher risk of psychosis for young adults and adolescents who took amphetamines for ADHD compared with those who took methylphenidate. In fact, those who took amphetamines had twice the risk of developing psychosis compared to individuals who took methylphenidate, according to the findings, which were published in NEJM.
“Amphetamine agents tend to be the class of stimulant medications more often associated with psychosis compared to methylphenidate formulation,” said Mitchell. “This may increase the need for monitoring for psychosis or mania when stimulant medications, particularly amphetamine formulations [dextroamphetamine, mixed amphetamine salts, amphetamine, or lisdexamphetamine] are prescribed at maximum or above maximum Food and Drug Administration recommended doses.”
Caley said he teaches his students that there is a pharmacologic difference between amphetamines and methylphenidate. “The primary way in which we see this difference manifest in patients is with dosing and symptom response,” he said. For instance, patients can be switched from one stimulant to the other if they do not respond to the first.
Other factors
Another piece to consider, according to Mitchell, is the use of cannabis, cocaine, methamphetamine, or hallucinogens and how these recreational drugs could impact psychosis or mania in patients, along with a family history of either set of symptoms. She said this warrants further investigation.
Moran said she assumed these associations would show up in the analysis, but they did not find any connections. They only noticed a connection with age when patients were aged 22 through 35 years, the risk for psychosis was greater.
Caley noted that adolescent and adult patients typically have a spectrum of what he calls “real world” confounders, such as comorbid substance, other psychiatric illnesses, or concurrently prescribed psychiatric pharmacotherapy. ■