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Acetaminophen, the ingredient found in hundreds of prescription and over-the-counter medicines — including Tylenol products — is routinely recommended for fever reduction and the relief of mild to moderate pain.
The link between acetaminophen and liver toxicity was established some time ago. But the drug’s effect on the developing nervous system in children — though suspected — was never formally investigated through a clinical study, according to William Parker, Ph.D., CEO of the nonprofit research firm WPLab.
Now, Parker’s new deep literature review has uncovered troubling associations between acetaminophen at typical pediatric doses and serious, likely permanent impairments in cognition and socialization in susceptible children.
The study, published last month in Clinical and Experimental Pediatrics, focused specifically on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).
In an interview with The Defender, Parker said one reason safety signals went unnoticed for years is that investigators were not looking at the right studies. “Most research to date has focused on acetaminophen use during pregnancy,” he said.
That makes sense, as developing fetuses are particularly vulnerable to drug-related (and other) toxicities.
“But no more than 20% of cases of ASD result from maternal use during pregnancy,” Parker said. “And the real number is probably more like 10% or even less. By far the greatest danger from this drug occurs after the child is born.”
Study identified 2 significant milestones suggesting link between acetaminophen and ASD
Parker has spent close to a decade tracking evidence connecting acetaminophen exposure early in life to ASD in susceptible babies and children.
His latest work examines 20 lines of evidence based on animal studies, connections between ASD and acetaminophen use, associations between acetaminophen and ASD through time, and what was already known about acetaminophen toxicity.
The main takeaways from animal studies:
- Long-term brain damage and behavioral changes occur following exposure to acetaminophen early in life, at doses similar or equal to those recommended for children.
- Acetaminophen affects the brains of male rats more than female rats; ASD also affects human males more than females.
- Acetaminophen kills brain cells in adult test animals at doses lower than required to cause liver damage.
Separately, Parker and coworkers tracked the incidence of ASD by year, noting two significant milestones that correlated with increases in its prevalence.
The first was the national campaign to replace aspirin with acetaminophen, which began in 1982 and continued in earnest for several years thereafter.
The second event was a substantial increase in direct-to-consumer pharmaceutical advertising (DTCPA) which began in earnest in 1981 but did not gain traction until after 1990. DTCPA increased from around $12 million in 1980, when it was still highly regulated, to $47 million in 1990, then $340 million in 1995 and $5 billion in 2006. DTCPA has leveled off in recent years, to just under $7 billion per year in 2021.
The pediatric research Parker reviewed reinforced his findings from the animal studies. To summarize:
- Despite its demonstrated toxicity to the nervous system in newborn laboratory animals, acetaminophen was tested in babies only for acute side effects, and not for nervous system development.
- Circumcision, for which acetaminophen is often taken as a painkiller, is associated with a dramatic increase in the risk for ASD.
- An unexpectedly high incidence of ASD was found in South Korea, where pediatric acetaminophen products often contained quantities of the drug that exceed recommended levels.
- Analysis of 61,430 babies in the Danish National Birth Cohort uncovered an increased risk of ASD of up to 66% after postnatal exposure to acetaminophen.
- Acetaminophen administered to reduce vaccine side effects was associated with ASD, even when vaccination alone was not.
- Factors known to enhance the toxicity of acetaminophen were associated with a higher risk of ASD. Genetics, for example, may affect an individual’s ability to eliminate acetaminophen from the body before it can cause harm.
- Oxidative stress can also exacerbate the drug’s effects. Conditions that induce oxidative stress include infections and various drug treatments. Parker noted that fasting enhances acetaminophen toxicity, a potential problem when a baby is too sick to eat.
- Acetaminophen use in early childhood is associated with a dramatic increase in ASD based on a small, case-controlled study.
- Many of the cognitive and social hallmarks of ASD are also seen temporarily in adults who have taken acetaminophen.
Brain is ‘main target’ organ for toxicity in newborns
This evidence was previously obscured for a variety of reasons. Some studies were simply ignored in literature reviews while others, including those connecting ASD and circumcision, never mentioned acetaminophen as a potential issue.
In another example, widespread accidental overdoses of acetaminophen in Korea were never connected with the country’s otherwise inexplicably high rates of ASD.
“Many healthcare industry professionals find it inconceivable that one of the most popular drugs ever is causing one of society’s thorniest behavioral problems,” Parker told The Defender.
“If they had employed investigative techniques similar to those used by law enforcement, rather than a reductionist biomedical approach, they probably would have noticed these connections much sooner,” Parker said.
He added: “A report that children with severe ASD could not safely process acetaminophen had already been published in 1999, but its significance was missed entirely, even by the study’s authors.”
The connection between ASD and acetaminophen use during vaccination was eventually identified in a 2008 study. However, according to Parker, “That study was largely ignored, with no follow-up from the National Institutes of Health, the CDC [Centers for Disease Control and Prevention], or the Pediatric Academy.”
In addition, most investigations on the effects of acetaminophen on the brains of infants and small children tended to focus on prenatal exposure which, although risky, accounts for just a small percentage of the neurologic damage caused by acetaminophen, according to Parker.
“And most of these focus on liver function, despite the fact that the brain rather than the liver is the main target organ for toxicity in newborns.”
A mother’s liver processes acetaminophen extremely efficiently, particularly during pregnancy. But newborns are deficient in a metabolic process, “glucuronidation,” involved in acetaminophen metabolism, which is why the association between ASD and acetaminophen use is stronger for postnatal as opposed to prenatal exposure.
Cats, interestingly, also have this metabolic disadvantage.
“Veterinarians know that there is no safe dose of acetaminophen for a cat. It’s profoundly troubling that pediatricians don’t know this about babies,” Parker said.
Available over the counter and also in 600+ prescriptions for kids, adults
Acetaminophen was discovered in 1878, and first identified as a possible analgesic at some point over the next ten to fifteen years. Due to the availability of other, presumably more effective medications, the drug was forgotten until the late 1940s, when it was rediscovered as a painkiller.
Acetaminophen became available in the U.S. by prescription only in 1953 and was launched by McNeil Laboratories in 1955 as Tylenol elixir, a pediatric analgesic available only by prescription.
Johnson & Johnson, after acquiring McNeil Laboratories, received approval in 1959 to market pediatric Tylenol formulations over the counter (OTC), and by 1961, Tylenol tablets for adults also entered the market as an OTC drug. By 1976, Tylenol had become the leading OTC pain reliever in the U.S.
More than 600 OTC and prescription pharmaceuticals, for both adults and children, contain acetaminophen. Although its main effects are fever reduction and pain relief, acetaminophen is often combined with other active ingredients to treat allergies, colds and cold symptoms, flu, and even sleeplessness.
Acetaminophen also is often combined with prescription painkillers to treat moderate to severe pain.
Acetaminophen use is associated with mild to moderate side effects that are common with OTC medicines, including agitation, constipation, headaches, insomnia, itchy skin and stomach irritation.
But many of those same symptoms are signs of serious liver injury, which for decades has been the most noted and studied side effect of the drug, particularly in individuals who consume alcoholic beverages or who take more than the recommended dose.
And, as Parker pointed out, babies are not just “small adults” when it comes to drug interactions.
“The antibiotic chloramphenicol is safe for adults, but caused the deaths of numerous infants in 1959.”
Acetaminophen has followed a similar trajectory.
Parker’s research showed that during the 1970s, when pediatricians were investigating the safe use of acetaminophen in babies and children, they almost exclusively focused on liver damage, not realizing that the drug primarily affects a baby’s brain, not their liver.
“Acetaminophen rapidly kills laboratory rat pups without hurting their livers, a fact that nobody knew when they started putting this into babies,” Parker said.
That the World Health Organization lists both acetaminophen (under the trade name paracetamol) and the antidote for acetaminophen overdoses as “essential medicines” is itself telling.
