Patients on High Dose Amphetamine Face Over 5-Fold Psychosis, Mania Risk

Patients on high doses of amphetamine face > 5-fold increased risk for developing psychosis or mania, a new study revealed.¹ The risk was the greatest for those taking ≥ 30 mg of dextroamphetamine, which equals 40 mg of Adderall.

“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 lead investigator Lauren Moran, MD, a pharmacoepidemiology researcher at McLean Hospital, in a press release.²

As an inpatient psychiatrist at McLean Hospital, Moran regularly observed patients who experienced their first episodes of psychosis while prescribed high doses of stimulants. Previous studies have linked stimulants to psychosis and mania risk but lacked information on whether dosing impacted the risk.

Moran and colleagues sought to examine the impact of dose levels of prescription amphetamines on the risk of psychosis or mania.¹ The team conducted a case-control study using electronic health records to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines.

The sample included patients aged 16 – 35 years who were hospitalized at McLean Hospital for incident psychosis or mania between January 1, 2005, and December 31, 2019. The control patients had an initial psychiatric hospitalization for other reasons, such as depression or anxiety. The study had 1374 case subjects and 2748 case subjects.

Case subjects were more likely to be male (P < .001), Black (P < .001), Hispanic (P = .004), have public health insurance (P < .001), have greater rates of cannabis use (P < .001), smoke tobacco (P = .002), and report past-month hallucinogen use (P < .001). Case subjects were less likely to report alcohol use disorder (P < .001), opioid use (P = .04), and sedative-hypnotic misuse (P = .005). Ultimately, case subjects had greater ADHD rates (P < .001).

In the study, investigators converted amphetamine doses to dextroamphetamine equivalents and divided them into terciles. A secondary analysis assessed the odds of psychosis or mania with methylphenidate use.

Patients on past-month amphetamine had increased odds of psychosis and mania, compared with controls (adjusted odds ratio [aOR], 2.68; 95% confidence interval [CI], 1.90 – 3.77), with a risk of nearly 63%. The team observed a dose-response relationship, with high doses of amphetamines (> 30 mg dextroamphetamine equivalents) linked to 5.28-fold increased odds of psychosis or mania. Patients on high-dose amphetamine had an 81% psychosis or manaia risk.

The team observed a significant effect modification by age (P = .03). Patients ≤ 22 years on amphetamine had lower odds of psychosis or mania (aOR, 2.26; 95% CI, 1.44 – 3.55) compared with those > 22 years (aOR, 4.10; 95% CI, 2.67 – 6.32). The team explained this may be due to the fact the older group had an average higher amphetamine dose.

Investigators found no significant effect modification by sex (females: aOR, 2.85; 95% CI, 1.73 – 4.69; males: aOR, 3.13; 95% CI, 2.09 – 4.70), cannabis use, family history of psychosis or mania, or any other covariates.

The secondary analysis revealed past-month methylphenidate use was not linked to increased odds of psychosis or mania compared with controls (aOR, 0.91; 95% CI, 0.51 – 1.55). This is consistent with findings from a previous study published in 2019 ed by Moran. An analysis that included only patients with past-month stimulant use, and adjusted for dose and covariates, showed amphetamine use was linked to increased odds of psychosis or mania compared with methylphenidate use (aOR, 2.85; 95% CI, 1.53 – 5.32).

Although this study does not prove causality, investigators observed a plausible biological mechanism in neurobiological changes: a release of greater levels of dopamine from amphetamines. The dopaminergic changes mimic changes observed in patients with psychosis.

Investigators wrote the study was limited by inconsistencies with how the electronic health records are stored and the lack of generalizability of the sample due to all the participants being admitted to the same psychiatry hospital that sees many patients with psychosis.

Despite the findings, Moran said the results should “not create alarm” but should expand caution when prescribing amphetamines, particularly for patients who have risk factors for psychosis and mania.

“There’s limited evidence that prescription amphetamines are more effective in high doses,” Moran said. “Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania.”

References

1. ^{Moran, LV et al. “Risk of Incident Psychosis and Mania with Prescription Amphetamines,” American Journal of Psychiatry. DOI: 10.1176/appi.ajp.20230329}
2. ^{High Doses of Some Prescription Stimulants Tied to Increased Psychosis Risk. Mass General Brigham. September 12, 2024.}