High-Dose Prescription Amphetamine Tied to Psychosis Risk

Teenagers and young adults taking high doses of prescription amphetamines may face a greater than fivefold increased risk of developing psychosis or mania, a new analysis suggests. 

The risk was highest with doses of ≥ 30 mg of dextroamphetamine, which corresponds to 40 mg of Adderall, investigators found. There was no association between new-onset psychosis or mania and past-month use of methylphenidate.

“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, lead investigator Lauren Moran, MD, a pharmacoepidemiology researcher at McLean Hospital, Belmont, Massachusetts, said in a news release. 

“This is a rare but serious side effect that should be monitored by both patients and their doctors whenever these medications are prescribed,” Moran said. 

The study was published online September 12 in the American Journal of Psychiatry. 

Clear Dose–Response Relationship

Previous studies have identified an increased risk of psychosis with prescription amphetamines, but information on the impact of dose levels is limited. 

“This represents a major gap in knowledge in light of high rates of prescribing of this class of medications,” write the researchers.

To investigate, Moran and colleagues conducted a case-control study using electronic health records of Mass General Brigham patient encounters between 2005 and 2019, focusing on individuals aged 16 to 35, the typical age of onset for psychosis. 

They identified 1374 case individuals who presented with a first episode of psychosis or mania and 2748 control patients with a psychiatric hospitalization for other conditions, most commonly depression or anxiety. 

Overall, they observed a greater than twofold increased odds of psychosis and mania among individuals with past-month prescription amphetamine use (adjusted odds ratio [aOR], 2.68; 95% CI, 1.90 – 3.77).

The likelihood of psychosis or mania with past-month prescription amphetamine use was increased by 5.3 times with doses exceeding 30 mg dextroamphetamine equivalents, which corresponds to 40 mg of mixed amphetamine salts and 100 mg of lisdexamfetamine. 

In sensitivity analyses comparing cases with outpatient controls, the odds of psychosis or mania were increased by 13.5 times with the highest dose level. 

Past-month use of methylphenidate was not associated with increased odds of psychosis and mania compared with no use (aOR, 0.91; 95% CI, 0.54 – 1.55), consistent with results from a 2019 study by Moran and colleagues. 

Risk Mitigation Strategies

Investigators noted in the study that current guidelines on attention-deficit hyperactivity disorder (ADHD) treatment lack maximum doses and recommend clinicians target the dose to symptom control while avoiding intolerable side effects, “given the lack of evidence-based research supporting maximum doses.”

“Our findings suggest that clinicians can mitigate the risk of psychosis or mania by avoiding doses above 30 mg dextroamphetamine equivalents,” they write. 

Commenting on the study for Medscape Medical News, Stephen Faraone, PhD, distinguished professor, Department of Psychiatry, Norton College of Medicine at SUNY Upstate Medical University, Syracuse, New York, noted that the US Food and Drug Administration already cautions that stimulants may cause psychosis. 

“These new data from a well-executed study provide some guidance about dose, which is helpful,” Faraone said. 

However, because most study participants did not have ADHD, it’s unknown if the data would apply to most people with that condition, he noted. 

“We also cannot tell if the stimulants were being used as prescribed,” Faraone added. “Because some patients abuse their stimulants, that could account for some of the results.” 

Faraone also cautioned that this was an observational study and, like all such research, is open to confounding. “The authors did a good job adjusting for available confounds but could not adjust for those that were not available such as severity of prior psychiatric disorders,” Faraone said. 

Also providing perspective, Nina Kraguljac, MD, professor, Department of Psychiatry and Behavioral Health, Ohio State University College of Medicine in Columbus, felt the study was “very carefully” performed and the authors did a “very good job describing the limitations of the research.”

“But as a researcher and clinician, my main takeaway is to be thoughtful when prescribing high doses of amphetamines for treatment of ADHD in younger populations, as the high-dose treatments can really increase the risk for psychosis,” Kraguljac told Medscape Medical News. 

This is especially important in cases when there is an existing family history of psychosis or other serious mental illness, Kraguljac said, “or choose an alternative medication like Ritalin [methylphenidate] in people where you’re concerned about family history of psychosis,” she advised. 

This work was funded by a grant from the National Institute of Mental Health. Moran is employed by Sage Therapeutics (unrelated to this work and after the study was completed and submitted for publication). Faraone and Kraguljac have reported no relevant relationships.