The FDA has approved only two drugs, both antipsychotics, for treating children with autism. Both are approved specifically for treating “irritability associated with autism.” However, doctors often also prescribe, off-label, other drugs, including stimulants and antidepressants, without the benefit of studies on how multiple drugs may interact.

Ten years ago, a Huffington Post investigation revealed that Johnson & Johnson had illegally promoted Risperdal, an antipsychotic drug associated with serious side effects, to children and the elderly.

Today, the drug remains one of only two medications approved by the U.S. Food and Drug Administration (FDA) to treat autism. The other is aripiprazole, also an antipsychotic, marketed as Abilify and sold by Bristol Myers Squibb.

According to the Huffington Post’s 15-part investigative report, the FDA had prohibited Johnson & Johnson salespeople from “trying to promote Risperdal to doctors to treat children because of its feared side effects, including hormonal disorders.”

Yet, the company “organized special sales units illegally targeting doctors who treated the elderly and children,” even as adverse events — including gynecomastia, which causes enlargement of breast tissue in males — were reported in some children who took the medication.

The reports led to thousands of lawsuits, with total settlements reaching several billion dollars.

The FDA first approved Risperdal (risperidone) to treat schizophrenia. That was in 1993. In 2006, the FDA approved the drug to treat “irritability” symptoms, including aggression and “temper tantrums,” associated with autism.

Research scientist and author James Lyons-Weiler, Ph.D, said the distinction between approving the drugs to treat autism versus treating “irritability associated with autism” is crucial.

Even though autism rates in U.S. children have sharply increased — from 1 in 10,000 in the 1970s to 1 in 31 in 2022 — Risperdal and aripiprazole remain the only FDA-approved drugs of their kind for people with autism.

According to Autism Speaks, the two FDA-approved medications don’t address autism’s core characteristics: difficulty with reciprocal communication, sensory integration challenges, repetitive patterns of behavior and atypical learning profiles,” which the organization calls “a huge area of unmet need.”

“The core traits of autism remain pharmacologically untouched,” Lyons-Weiler said. “We’re applying treatments designed for major depressive disorder, schizophrenia, epilepsy and generalized anxiety disorder to developing children with a completely different etiology and neurobiology.”

Several other types of medications are commonly prescribed “off-label” to patients with autism, meaning the drugs have FDA approval, but are not approved to treat autism symptoms.

Pediatrician Dr. Michelle Perro said these medications include “antipsychotics, stimulants, selective serotonin reuptake inhibitors (SSRIs) and melatonin.” The drugs are prescribed to “manage associated symptoms such as irritability, aggression, hyperactivity, anxiety, and sleep disturbance.”

Lyons-Weiler said “off-label prescribing is the rule, not the exception, in autism care” — but noted that it’s practiced “in the absence of data on long-term safety.”

Studies have shown that children with autism are more susceptible to adverse events. There are few studies on how these drugs interact when taken together, even though the practice of prescribing multiple drugs, known as polypharmacy, is also associated with an increased risk of adverse events.

“The existing pharmacologic model for autism is not a treatment paradigm — it’s behavioral sedation, selectively applied,” Lyons-Weiler said.

As of 2022, Risperdal was the 183rd most commonly prescribed medication in the U.S., although usage fell by more than half since its peak in 2014.

Off-label drugs for autism symptoms lack clinical trials

FDA-approved and drugs prescribed off-label for autism-related symptoms are all associated with severe adverse events.

Antipsychotic medications, including Abilify, Risperdal and Zyprexa, are commonly prescribed for aggression, irritability and repetitive behaviors.

Common side effects associated with antipsychotics range from drowsiness, dizziness and weight gain to seizures, low blood pressure and sexual problems. These medications are also associated with high blood sugar, stroke and thoughts of suicide or self-harm.

This category of drugs “alter neurotransmitter activity broadly and are linked to metabolic syndrome, prolactin elevation, gynecomastia and profound weight gain,” Lyons-Weiler said.

Perro said the drugs can also lead to “exacerbation of underlying motor issues.”

Antidepressants, or selective serotonin reuptake inhibitors (SSRIs), improve levels of serotonin — a hormone and neurotransmitter that regulates mood. These drugs, including Celexa, Prozac and Zoloft, are prescribed to children with autism to reduce anxiety, depression and the frequency or intensity of repetitive behaviors.

But according to Lyons-Weiler, “SSRIs are often ineffective and can induce agitation, emotional blunting, or even suicidal ideation — especially in pediatric populations.”

Autism Speaks acknowledges that “large clinical trials have yet to demonstrate” the effectiveness of SSRIs in treating autism symptoms.

While common side effects of SSRIs include diarrhea, fatigue, nausea and weight gain, the medications also are associated with serious adverse events, including heart rhythm changes, bleeding and thoughts of suicide or self-harm.

“SSRIs may help repetitive behaviors, but they can also increase social withdrawal and cause further emotional blunting,” Perro said.

Stimulants — which address hyperactivity and a lack of attention and focus — are also commonly given to children with autism. These can include Adderall, Ritalin and Vyvanse.

Stimulants increase the levels of dopamine and norepinephrine, the hormones and neurotransmitters involved in key bodily functions and the regulation of emotions.

Common side effects of stimulants include decreased appetite, headaches, sleep problems and stomach aches.

Stimulants also are linked to more serious adverse events, including heart rhythm changes, increased blood pressure, seizures, stroke and Raynaud’s disease, a condition that occurs when blood doesn’t flow properly to the fingers and toes.

And according to Lyons-Weiler, “Stimulants may increase anxiety, aggression or tics, especially in children with immune or gut-brain axis disturbances.”

‘An uncharted pharmacologic wilderness’

While the adverse event profile of specific medications is well known and noted on each respective drug’s package inserts, significantly less information is known about potentially harmful adverse events that may result from interactions between multiple medications when taken together to treat autism-related symptoms.

According to an article published last month in The Conversation, polypharmacy “has become more of an issue for autistic people” in recent years.

“Polypharmacy exacerbates these risks, yet remains underregulated,” Lyons-Weiler said. “Children are often on three, four, five or more psychoactive agents simultaneously, without a single randomized control trial to guide those combinations. When used in isolation, these drugs already carry serious side effects. When combined, we enter an uncharted pharmacologic wilderness.”

According to Lyons-Weiler, serious adverse events associated with polypharmacy of medications to treat autism symptoms include:

• Cognitive stagnation, including lowered processing ability
• Endocrine disruption, including delayed puberty and suppressed testosterone
• Metabolic effects, including insulin resistance, cholesterol changes and rapid weight gain
• Neurological side effects, including movement disorders and sedation
• Worsened behavior

“These outcomes are too often treated as unrelated comorbidities — when in fact, they may be iatrogenic,” Lyons-Weiler said. “This is why polypharmacy without a systems-based understanding of detoxification, metabolism and neuroinflammation is dangerous. It treats symptoms as siloed entities, not as expressions of a larger disrupted system.”

Lyons-Weiler said only a small number of studies examining the effects of polypharmacy on autistic children exist.

A study published in the journal Research in Autism Spectrum Disorders in 2020 found that autistic youth in New Zealand were more likely to experience side effects than non-autistic youth, in part because these youth “experience a significant medication burden” — with over half the youth studied taking three or more medications simultaneously.

A subsequent study published in the same journal in 2022 found that “Children with autism and ADHD experience significant medication burden and potentially adverse interactions between psychotropic and sleep-related medication, raising important questions regarding their clinical care.”

According to a 2019 systematic review and meta-analysis published in the journal Pediatric Drugs, heightened sensory and nervous system sensitivities in autistic patients may account for the increased prevalence of side effects.

And a study published last year in the journal Autism found that people with autism had a mortality risk more than double that of the general population.

Pharma reaps big profits from drug-based treatments for autism

According to Lyons-Weiler, while existing drug-based treatment routes for autistic patients have proven problematic, more successful treatments are being overlooked, because “these are not ‘prescribable’ — and thus, they are not reimbursable, and thus they are not ‘mainstream.’”

“Pharmaceutical interventions are easy to prescribe, reimburse and codify into protocols,” he said. “What’s neglected are the therapies that treat the child as a biological system, not a behavioral problem.”

According to Perro, “These therapies may include dietary changes, homeopathics, probiotics, detoxification protocols and targeted supplements, concomitantly with therapies that focus on reducing inflammation and promoting gut health, helping to improve both behavioral and physical outcomes for children with autism spectrum disorder.”

Lyons-Weiler suggested that reducing exposure to known immune system disruptors in the environment can also help autistic patients.

“But these interventions don’t fit the CPT [current procedural terminology] billing model or the double-blind placebo-controlled randomized control trial framework neatly — so they remain in the shadows,” Lyons-Weiler said.

He called for “practical, applied, systems-level research” operating outside the influence of pharmaceutical interests, with complete data transparency and replication incentives built into the research design.

According to Perro, “A key area of research which has not been adequately explored looks at identifying various biomarkers … that could predict treatment responses or side effects.”

She also called for more long-term safety studies, longitudinal studies, head-to-head trials and studies exploring non-pharmacological treatments.

In April, the National Institutes of Health (NIH) announced the launch of a new research program to study the causes of autism and the increase in diagnoses.

Last month, NIH and the Centers for Medicare & Medicaid Services announced a “landmark partnership” allowing NIH researchers to analyze the health records of children and adults enrolled in Medicare or Medicaid who have an autism diagnosis.

Lyons-Weiler said more is needed than just further scientific and clinical studies.

“This won’t happen through pharmaceuticals alone. It requires listening to families, integrating real-world evidence, and respecting biology’s complexity rather than bypassing it,” Lyons-Weiler said.

“We owe it to the children who never got to find out who they could have been. We owe it to the parents who ask not for miracles, but for science that’s honest, brave and complete.”