The beta-blocker propranolol (multiple brands) may improve social and cognitive impairment for patients with autism spectrum disorder (ASD), new research suggests.
Investigators found that for patients with autism, propranolol improved performance on a word generation test compared to placebo, and brain imaging results revealed that the drug altered regions of the brain associated with word processing and improved specific task information processing.
"In this study, we used fMRI to look at functional connectivity between language regions during a language task to examine the effects of propranolol in the brain in ASD," study investigator David Beversdorf, MD, professor of radiology, neurology, and psychology at the University of Missouri School of Medicine and the Thompson Center, in Columbia, told Medscape Medical News.
"We found that propranolol altered the functional connectivity in these networks such that the connectivity during these tasks resembled that of unaffected individuals," he said.
The study was published online August 15 in Autism.
Mitigating Social Anxiety
The autonomic nervous system (ANS) may contribute to ASD, as suggested by reports of heightened sympathetic nervous system (SNS) arousal/stress reactivity and reduced parasympathetic nervous system (PNS) tone in people with ASD, the authors write.
The PNS modulates SNS activity — an effect that may be reduced in ASD — so pharmacologic modulation of the SNS "may provide some clinical benefit," said Beversdorf.
"Propranolol might help ASD by mitigating social anxiety, much like the drug is used for test anxiety and performance anxiety, and may also have a fundamental effect on brain networks, allowing more flexible performance in social situations," he said.
Propranolol is a central nervous system and peripheral nervous system beta-blocker that crosses the blood-brain barrier.
"We had previously performed single-dose challenge studies suggesting a beneficial effect of propranolol on language task performance in ASD," Beversdorf reported.
Because ASD is "characterized by altered functional connectivity patterns in the brain, we wanted to determine whether propranolol affected these networks during language tasks, in order to begin to understand its effects," he said.
To investigate, the researchers compared 13 individuals with ASD to 13 matched typically developing (TD) control persons.
The groups did not significantly differ from one another in age (mean [SD], 22.23 years [4.6 years] and 22.86 years [2.68 years], respectively); sex (11 males and two females in each group); full-scale intelligence quotient; years of education; ethnicity; handedness; or family income (all Ps > .05).
The patients participated in three "counterbalanced" sessions, in which they received one drug — propranolol or nadolol (multiple brands; nadolol is another beta-blocker that does note cross the blood-brain barrier) — or placebo per session.
Participants underwent electrocardiography, and their heart rate (HR) and blood pressure (BP) were measured.
During fMRI, participants completed a task that assessed semantic fluency. The task required naming as many as items as possible that belonged to a particular category.
The imaging enabled assessment of functional connectivity in the brain.
Potential Side Effects?
TD control persons exhibited better performance on the semantic fluency task than did individuals with ASD, and the control persons had higher scores on average across all sessions, including sessions in which they received placebo (F[1, 24] = 25.67, P < .001, η2 p = .23; and 2 = 0.23 and MASD = 27.31 [5.84], MTD = 41.69, [10.50]; t  = −5.03, P < .001, d = 1.69).
Participants with ASD also exhibited hyperconnectivity in the FPC, which was associated with poorer performance on the task.
When treated with propranolol, all participants exhibited improved performance. The benefit was accompanied by "increased efficiency" of subnetwork processing in the SAN.
In addition, the hyperconnectivity of the FPC shown by participants with ASD was "ameliorated" after the administration of propranolol — a change in FC that was associated with the magnitude of the baseline hyperconnectivity.
"Thus, it appears that some performance benefits from β-adrenergic antagonism may be associated with increased functional integration of domain-specific networks in the brain," the authors write.
Additionally, the HR (beats/minute) during sessions in which participants received placebo was significantly associated with the performance benefit from propranolol (r = −0.53, [.76 to −.18], P = .01).
When controlling for baseline PNS tone, the researchers found that the drug-mediated alterations did not hold, "suggesting that inherent ANS regulation may be involved," they write.
"Baseline activity of the autonomic nervous system appeared to predict who responds [to propranolol]," said Beversdorf.
He pointed out that propranolol has some side effects, including lowered blood pressure and heart rate, "so individuals that are too low on these parameters should be cautious about using the drug."
Moreover, "it can worsen asthma and increase depression," he said.
He noted, "One advantage is that the drug has been around for over 50 years, so at least we are quite familiar with its range of side effects."
Commenting on the study for Medscape Medical News, Daniel Rossignol, MD, a physician with a private practice in Melbourne, Florida, who was not involved with the study, called the findings "novel."
"Studies on propranolol in individuals with autism have reported a number of improvements in speech, cognition, memory, hypersexual behaviors, anxiety, aggression, social interaction, and eye contact," said Rossignol, who is on the editorial board of the Journal of Autism and Epilepsy.
The current study "reinforces the findings from previous studies and further reports that propranolol improves the functional connections in certain areas of the brain associated with information processing," he said.
The take-home message, he said, is that the use of propranolol in individuals with autism "appears to be a safe way to improve brain function and speech."
Currently, no treatments to improve these domains for people with autism have been approved by the US Food and Drug Administration (FDA). Thus, "this medicine represents a novel treatment that might eventually be FDA-approved for treating some of the core symptoms of autism-impaired social communication and restricted/repetitive behavior," he added.
Rossignol acknowledged the potential side effects of fatigue and decreased BP and HR, but stated that these effects can usually "be minimized by starting with a small dose and increasing over time as tolerated."
Given that some persons with autism "have significant improvements with beta-blockers, such as decreased aggression, hypersexual behaviors, and anxiety, as well as increased speech and cognitive function, the benefits may outweigh the risk for many children," Rossignol said.
Beversdorf said the study sheds potential light on the drug's underlying mechanism in autism.
"While this [study] and our single-dose challenge studies are of interest, recommendations for practicing clinicians would need to await the results of a clinical trial, and we are currently conducting this trial," he said.
The study was supported by a grant from the Health Resources and Services Administration, the University of Missouri School of Medicine Mission Enhancement Fund, the National Institute on Alcohol Abuse and Alcoholism, the University of Florida Center for Cognitive Aging and Memory, the McKnight Brain Research Foundation, and the University of Missouri Molecular Life Sciences Predoctoral Fellowship Program. Beversdorf and coauthors and Rossignol report no relevant financial relationships.
Autism. Published online August 15, 2019. Abstract
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