Amphetamine use has risen steadily in the US over the past few years – up 70% between 2011 and 2021 – with a recent study suggesting that people taking high doses of these drugs have a five-fold increased risk of developing psychosis, or mania, which may even lead to schizophrenia.
There was an even larger spike in use of the drugs during the Covid-19 pandemic, according to researchers from McLean Hospital in Massachusetts, whose study was published in the American Journal of Psychiatry.
Psychosis risk increases 81% on high-dose amphetamines, they said, after analysing medical data from adults between 16 and 35 who were treated at Mass General Brigham between 2005 and 2019.
From this pool, the scientists identified about 1 300 people presenting with a first-episode psychosis or mania, and another about 2 700 people – considered the control group – with a psychiatric hospitalisation for other conditions, like depression or anxiety.
Researchers also examined study participants’ stimulant use, as well as any other factors that might influence that amount, such as substance abuse.
At the study’s conclusion, the team found that participants receiving any prescription amphetamine had a 63% risk of developing psychosis or mania. That percentage increased to 81% for those taking high-dose amphetamine, considered 30mg or more.
According to the researchers, the findings suggest that 81% of psychosis or mania cases in people taking prescription amphetamines could have been eliminated if they were not taking a high dose.
“Stimulant medications don’t have an upper dose limit on their labels, and our results show it is clear that dose is a factor in psychosis risk and should be a chief consideration when prescribing stimulants,” said Lauren Moran, MD, a pharmaco-epidemiology researcher at McLean Hospital, and lead study author.
“This is a rare but serious side effect that should be monitored by both patients and their doctors whenever these medications are prescribed,” she added.
Researchers also reported no significant psychosis or mania risk increase in study participants receiving methylphenidate, commonly known by one of its brand names, Ritalin. This finding was consistent with previous research led by Moran in 2019, they said.
“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.”
David Merrill, MD, PhD, a board-certified geriatric psychiatrist at Providence Saint John’s Health Centre in Santa Monica, California, and Singleton Endowed Chair in Integrative Brain Health, told Medical News Today that the association of high-dose amphetamine use with an increased risk of psychosis or mania was a reminder of the need for careful patient selection, dose titration, and close monitoring.
“This study prompts an immediate reconsideration of risk-benefit analysis in the prescribing process, particularly for patients with a history of mental health issues or those at high risk for psychosis,” he warned.
“These findings underscore the need to use the lowest effective dose, initiate treatment with extended-release formulations to minimise peak plasma levels, and emphasise non-pharmacologic interventions as first-line treatments whenever possible.
“Additionally, with stimulant use there is a need for regular mental health evaluations and more frequent follow-ups, especially during the initiation and titration phases of amphetamine therapy. Particular care taken when considering the drugs’ in patients with a history of psychosis, bipolar disorder, or other psychiatric vulnerabilities.”
Stacy Doumas, MD, MBA, chairwoman of Psychiatry at Hackensack Meridian Jersey Shore University Medical Centre and vice chairwoman and associate professor in the Department of Psychiatry at Hackensack Meridian School of Medicine, who was not involved in the study, said the findings were concerning, but not surprising.
“Given the activity of amphetamines on the neurotransmitters in the brain, such as dopamine, which are also related to psychosis, there are potential mechanisms to explain this. It’s a great study that starts to look more closely at associations between stimulant classes and psychosis.”
“You always want to be looking at the evidence base for what you are prescribing, especially with the perspective of avoiding harm.
“First-episode psychosis and mania often present in late adolescence to early adulthood. This is often when prescriptions of stimulants are being written for patients for attention deficit hyperactivity disorder (ADHD). Although psychosis remains a rare side effect, the study did describe an increased, dose dependent risk with amphetamines that was not seen with methylphenidate use.
Future studies are indicated to help identify whether this is a casual relationship.”
She suggested researchers should explore whether there is a clear casual relationship between high-dose amphetamine prescriptions and the risk of psychosis and mania.
“There are several types of future studies to consider,” she added. “Longitudinal cohort studies tracking the mental health of individuals taking antipsychotics over time compared with controls would provide valuable information… but would take years to complete.”
“Pharmacovigilance studies would allow researchers to look at existing databases to analyse amphetamine prescription patterns and cases of psychosis.
“Mechanistic studies can also further explore biological mechanisms relating amphetamines to neurotransmitters – like dopamine – that have a role in psychosis. This research could help inform of the risk of psychosis or mania associated with amphetamine use.”
Study details
Risk of Incident Psychosis and Mania With Prescription Amphetamines
Lauren Moran, Joseph Skinner, Ann Shinn et al.
Publlshed in American Journal of Psychiatry on 12 September 2024
Abstract
Objective
Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome.
Methods
A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16–35 hospitalised at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalisation for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use.
Results
Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90–3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54–1.55).
Conclusions
Although use of hospitalised control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.
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