It is true that our understanding of science is always changing. However, our understanding is changing at the frontiers of science. As science progresses, some information that was at the frontiers becomes conclusively established. It becomes a fact of science. Great examples of this are that the sun is at the center of our solar system, the heart pumps blood around our body, and men are not inherently smarter than women. These facts of today were poorly understood and hotly contested in the past.
As of July of 2024, we have compiled a total of 24 lines of evidence telling us without reasonable doubt that exposure of susceptible babies and children to acetaminophen causes many if not most cases of autism spectrum disorder (ASD). Those twenty-four lines of evidence were gleaned from over a decade of study of thousands of publications. Without reasonable doubt, we conclude that the causal relationship between acetaminophen and autism is a scientific fact. That won’t change.
More evidence continues to surface
Even still, what we know about the science of the acetaminophen/autism connection is still growing. New evidence surfaces on a regular basis. For example, in November of 2024, scientists found that exposure of laboratory rats to acetaminophen during pregnancy causes problems with the processing of sound in a way that is similar that seen in many individuals with autism [1].
That’s line of evidence number 25.
Other lines of evidence have yet to be added to our list. For example, acetaminophen is known to react in multiple ways with a molecule in the body called arachidonic acid. Acetaminophen prevents arachidonic acid from being converted into an important chemical called prostaglandin E2, resulting in an anti-fever effect*. Acetaminophen even binds directly to arachidonic acid, forming a molecule called AM404, which blocks pain. And, in a finding published in September of 2024, alterations of arachidonic acid are associated with autism [2].
That’s line of evidence number 26.
Another line of evidence is related to the genetics of autism. A study of the Swedish population showed that men with autism had only 25% as many children as other men [3]. This finding tells us that, if autism was due to specific genetic markers, then autism is likely to have been “selected out” of the human population long ago. How could a condition associated with such a dramatic decrease in child-bearing be as prevalent as one in 36? If autism is genetically determined, then the answer must lie in a complex interaction of literally hundreds of genes associated with autism. But, studies of the genetics of autism do NOT support this solution. This conundrum leads to what is known as the paradox of “missing heritability” in autism [4]. Studies in siblings suggest that autism is mostly genetic, but the combination of genes involved simply can’t be identified.
One resolution of the paradox lies in the environment. As Brendan Maher points out [4], if the environment in the womb (or, I’ll point out, at the time of birth) interacts with genetics, then a condition that seems to be genetic based on sibling studies can actually be triggered environmentally. In addition, the environment of the mother when she was a child and perhaps even the environment of her parents when they were young can affect the environment in the womb. The fact that abuse of a mother when she was a child is associated with autism in the offspring [5] supports this view.
Thus, the interaction of acetaminophen with a wide range of genetic, epigenetic, and environmental factors resolves the paradox of missing heritability in autism.
That’s line of evidence Number 27.
While we have not yet compiled these lines of evidence into our list in the peer reviewed literature, they add to a body of evidence that is already overwhelming, and provide additional insight into the connection between acetaminophen and neurodevelopment.
As always, we want to emphasize that no single line of evidence by itself is conclusive. It is the weight of total evidence that is overwhelming.
Refining the twenty-four
Most of the new evidence we find regarding the connection between acetaminophen and autism does NOT constitute a new line of evidence, but it reinforces or refines an old line of evidence. A great example of this is a study published in 2023 from Columbia University showing that early-life exposure of male mice to acetaminophen has greater long-term impact than exposure of female mice to the drug [6]. Thus, the sex-bias of acetaminophen-induced injury on laboratory animals matches the sex-bias of autism. That’s a line of evidence. But we already knew from work in laboratory rats at the University of Maryland, published more than a decade earlier, that male laboratory rats are more sensitive than female laboratory rats to developmental injury caused by drugs that have some of the same effects as acetaminophen [7]. This means that the newer study from Columbia did not add a new line of evidence, but it did very nicely reinforce an old line of evidence first established at the University of Maryland.
Some recently published work on the autism/acetaminophen connection from our lab focused on two particular lines of evidence dealing with associations between autism and acetaminophen use gleaned from analysis of healthcare databases. Our focus on these lines of evidence was triggered by a paper published in the journal JAMA in April of 2024 claiming that no associations exist between acetaminophen use during pregnancy and autism [8]. Our group, in turn, published a follow-up analysis demonstrating a fundamental flaw in the JAMA paper [9]. But that paper from our lab still isn’t the last word on this topic.
We recently worked with editors at the journal Integrative Medicine, publishing an interview describing our experiences working on the connection between acetaminophen and autism [10]. In that paper, we point out that Cuba has chronic shortages of all medications, and apparently has a very low prevalence of autism. This was pointed out to us by Dr. Bill Shaw, and does not add a new line of evidence. Rather, it supports an existing line of evidence based on the low prevalence of autism in several other ultra-low income countries [9].
Here is a great spot to point out that most of the lines of evidence we have compiled do NOT come from WPLab. We have produced a couple of lines of evidence, provided experimental support for another line of evidence, and provided proof that two other lines of evidence are valid. We have also provided support for the work of others that has been unreasonably questioned. But Dr. Shaw is one of many scientists who have provided most of the lines of evidence we have compiled.
We also refine our previous work as needed. As with most scientific papers, ours are not perfect. For example, due to typesetting errors during publication, one of our papers contained references in a table that were misdirected [11]. Due to errors during editing, another paper has the number 2.5000 in place of the number 2. 667 [9]. (Ironically, if we had used the correct number, the results would have even been more impressive.) A more common problem is that we can be unaware of very recent work and, as a result, fail to cite other scientists who have contributed to the field. In those cases, I usually reach out to the authors of the study and apologize for not giving them appropriate credit. These sorts of imperfections have no effect on our conclusions, but they do give us room for improvement.
So, with each paper, we cover more information, and we cover it more accurately and in more detail. However, even as the science changes at the frontier, maturing and coming into better focus, we conclude without reasonable doubt that the facts of the situation will not change: Exposure of susceptible babies and children to acetaminophen causes many if not most cases of autism.
If you would like to learn more about how you can help in preventing autism, you can read more here.
*Fevers are a protective response from the immune system, and there is no scientific evidence that blocking that response with acetaminophen is helpful [12, 13].
1. Graeca M, Kulesza R. Impaired brainstem auditory evoked potentials after in utero exposure to high dose paracetamol exposure. Hear Res. 2024;454:109149. Epub 2024/11/18. doi: 10.1016/j.heares.2024.109149. PubMed PMID: 39550993.
2. Hirai T, Umeda N, Harada T, Okumura A, Nakayasu C, Ohto-Nakanishi T, et al. Arachidonic acid-derived dihydroxy fatty acids in neonatal cord blood relate symptoms of autism spectrum disorders and social adaptive functioning: Hamamatsu Birth Cohort for Mothers and Children (HBC Study). Psychiatry and clinical neurosciences. 2024;78(9):546-57. Epub 2024/07/23. doi: 10.1111/pcn.13710. PubMed PMID: 39041066; PubMed Central PMCID: PMCPMC11488600.
3. Power RA, Kyaga S, Uher R, MacCabe JH, Långström N, Landen M, et al. Fecundity of Patients With Schizophrenia, Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings. JAMA Psychiatry. 2013;70(1):22-30. doi: 10.1001/jamapsychiatry.2013.268.
4. Maher B. Personal genomes: The case of the missing heritability. Nature. 2008;456(7218):18-21. doi: 10.1038/456018a.
5. Roberts AL, Lyall K, Rich-Edwards JW, Ascherio A, Weisskopf MG. Maternal exposure to childhood abuse is associated with elevated risk of autism. JAMA psychiatry. 2013;70(5):508-15. doi: 10.1001/jamapsychiatry.2013.447. PubMed PMID: PMC4069029.
6. Baker BH, Rafikian EE, Hamblin PB, Strait MD, Yang M, Pearson BL. Sex-specific neurobehavioral and prefrontal cortex gene expression alterations following developmental acetaminophen exposure in mice. Neurobiol Dis. 2023;177:105970. Epub 2022/12/23. doi: 10.1016/j.nbd.2022.105970. PubMed PMID: 36549432; PubMed Central PMCID: PMCPMC9940030.
7. Dean SL, Knutson JF, Krebs-Kraft DL, McCarthy MM. Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period. Eur J Neurosci. 2012;35(8):1218-29. Epub 2012/04/20. doi: 10.1111/j.1460-9568.2012.08032.x. PubMed PMID: 22512254; PubMed Central PMCID: PMCPmc3534986.
8. Ahlqvist VH, Sjöqvist H, Dalman C, Karlsson H, Stephansson O, Johansson S, et al. Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability. Jama. 2024;331(14):1205-14. Epub 2024/04/09. doi: 10.1001/jama.2024.3172. PubMed PMID: 38592388; PubMed Central PMCID: PMCPMC11004836 Neobiomics AB, a startup company located at the Karolinska Campus that works with niche food supplement solutions for infants. Dr Gardner reported receiving grants from Swedish Research Council during the conduct of the study. Dr Lee reported receiving personal fees from Beasley Allen Law Firm, Patterson Belknap Webb & Tyler LLP, and AlphaSights and grants from NIH (1R01NS107607) during the conduct of the study and grants from NIH (1P50HD11142-01, 3 P50HD111142-02S1, 1 R01 NS131433-01), Pennsylvania Department of Human Services, US Department of Defense, and Pennsylvania Department of Health CURE SAP (# 410008574)7 outside the submitted work. No other disclosures were reported.
9. Jones JP, 3rd, Williamson L, Konsoula Z, Anderson R, Reissner KJ, Parker W. Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder. Life (Basel, Switzerland). 2024;14(8). Epub 2024/08/31. doi: 10.3390/life14080918. PubMed PMID: 39202661; PubMed Central PMCID: PMCPMC11355895.
10. Baker S. An Interview with Dr. William Parker on the Connection between Acetaminophen and Autism. Integrative medicine (Encinitas, Calif). 2024;23(5):42-7. Epub 2024/11/14. PubMed PMID: 39534665; PubMed Central PMCID: PMCPMC11552961.
11. Parker W, Hornik CD, Bilbo S, Holzknecht ZE, Gentry L, Rao R, et al. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. J Int Med Res. 2017;45(2):407-38.
12. Patel E, Jones Iii JP, 3rd, Bono-Lunn D, Kuchibhatla M, Palkar A, Cendejas Hernandez J, et al. The safety of pediatric use of paracetamol (acetaminophen): a narrative review of direct and indirect evidence. Minerva pediatrics. 2022;74(6):774-88. Epub 2022/07/14. doi: 10.23736/s2724-5276.22.06932-4. PubMed PMID: 35822581.
13. Parker W, Anderson LG, Jones JP, Anderson R, Williamson L, Bono-Lunn D, et al. The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits. Children. 2024;11(1):44. PubMed PMID: doi:10.3390/children11010044.