High-dose ADHD drugs linked to 81% higher psychosis risk, study warns

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Amphetamines are a drug used to commonly treat attention deficit hyperactivity disorder (ADHD) and narcolepsy.
Past studies link amphetamine use to possibly developing the psychiatric disorder psychosis.
Researchers from McLean Hospital have found that people who take high doses of amphetamines have a five-fold increased risk of developing psychosis or mania.
Amphetamines are a type of stimulant drug that energizes the central nervous system. They are prescribed to treat conditions such as attention deficit hyperactivity disorder (ADHD), narcolepsy, depression, and obesity.
Amphetamines
central nervous system
attention deficit hyperactivity disorder (ADHD)
narcolepsy
depression
obesity
Previous research shows that prescription amphetamine use in adults has been increasing in the United States, increasing 70% from 2011 to 2021, with a larger spike during the COVID-19 pandemic.
70%
COVID-19 pandemic
There are a number of potential side effects to taking amphetamines, including possible addiction, especially if used illegally as a recreational drug.
illegally
Past studies have also linked amphetamine use to possibly developing the psychiatric disorder psychosis, which in some cases may lead to schizophrenia.
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psychosis
schizophrenia
Now, researchers from McLean Hospital in Massachusetts have found that people who take high doses of amphetamines have a five-fold increased risk of developing psychosis or mania.
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Their study was recently published in the American Journal of Psychiatry.
American Journal of Psychiatry
Psychosis risk increases 81% on high-dose amphetamine
For this study, researchers analyzed medical data from adults between the ages of 16 and 35 treated at Mass General Brigham between 2005 and 2019.
From this pool, 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 hospitalization for other conditions such as 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 research team found that study 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 30 milligrams (mg) 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 that 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 pharmacoepidemiology researcher at McLean Hospital, and lead study author in a press release.
Lauren Moran, MD
press release
“This is a rare but serious side effect that should be monitored by both patients and their doctors whenever these medications are prescribed,” she emphasized.
Researchers also reported there was no significant psychosis or mania risk increase in study participants receiving methylphenidate, commonly known by one of its brand names, Ritalin. This finding, scientists say, was consistent with previous research led by Moran in 2019.
methylphenidate
previous research
“There’s limited evidence that prescription amphetamines are more effective in high doses,” Moran said in the press release. “Physicians should consider other medications our study found to be less risky, especially if a patient is at high risk for psychosis or mania.”
Are the benefits of taking these ADHD drugs really worth the risk?
After reviewing this study, David Merrill, MD, PhD, a board-certified geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, CA, 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 reminds us of the need for careful patient selection, dose titration, and close monitoring.
David Merrill, MD, PhD
“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,” Merrill explained.
“These findings underscore the need to use the lowest effective dose, initiate treatment with extended-release formulations to minimize peak plasma levels, and emphasize nonpharmacologic interventions as first-line treatments whenever possible,” he further suggested.
“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. There needs to be particular care taken when considering use of amphetamines in patients with a history of psychosis, bipolar disorder, or other psychiatric vulnerabilities.”
bipolar disorder
– David Merrill, MD, PhD
“It will be important to study and report on longitudinal long-term outcomes of patients on amphetamines,” Merrill added. “We need to further define the specific risk factors that predispose individuals to psychosis or mania when exposed to amphetamines, such as genetic markers, pre-existing mental health conditions, or concurrent use of other substances.”
Amphetamines and psychosis: Is the relationship causal?
MNT also spoke with Stacy Doumas, MD, MBA, chairwoman of Psychiatry at Hackensack Meridian Jersey Shore University Medical Center and vice chairwoman and associate professor in the Department of Psychiatry at Hackensack Meridian School of Medicine in New Jersey, about this study.
Stacy Doumas, MD, MBA
“The study is concerning, but not surprising,” Doumas, who was not involved in the research, told us. “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.”
neurotransmitters
dopamine
“As a prescriber, you always want to be looking at the evidence base for what you are prescribing, especially with the perspective of avoiding harm,” she continued.
“First-episode psychosis and mania often present in late adolescence through early adulthood. This is a common time when prescriptions of stimulants are being written for patients for attention deficit hyperactivity disorder. 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.”
– Stacy Doumas, MD, MBA
For the next steps in this research, Doumas commented that 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 continued. “Longitudinal cohort studies tracking the mental health of individuals taking antipsychotics over time compared to controls will provide valuable information, but would take years to complete.“
“Pharmacovigilance studies would allow researchers to look at existing databases to analyze amphetamine prescription patterns and cases of psychosis,“ Doumas pointed out.
Pharmacovigilance
“Mechanistic studies can also further explore biological mechanisms relating amphetamines to neurotransmitters such as dopamine that have a role in psychosis. Together, this research could help inform of the risk of psychosis or mania associated with the use of amphetamines,” she concluded.