Those of you who are interested in the nuts and bolts of scientific research may want to read all of evidence in the original scientific papers telling us that exposure of susceptible babies and children to acetaminophen causes many if not most cases of autism. Because science evolves over time, and because the evidence has accumulated to a point that it literally will not fit into one paper, all of the evidence cannot be conveniently found in one place.
In this letter, I’ll explain what happened over time, and I’ll point you to specific review papers covering specific topics of interest. Here I’ll only discuss our five narrative reviews, which are the most comprehensive summaries of the topic. We have published other research on the topic, but that work is more limited in scope than the reviews.
Summary:
For those who want the overview: Please see our 24 lines of evidence
For parents and guardians wanting some context: Please read our parents and guardian’s guide to acetaminophen and autism
For the scientifically or medically inclined: please read on
Read the evidence for yourself
Our first comprehensive review of the connection between acetaminophen and autism was first submitted for publication in June of 2016, and was eventually published in early 2017 here: https://pubmed.ncbi.nlm.nih.gov/28415925/ That paper contains a very detailed description of the factors that interact with acetaminophen, leading to neurodevelopmental injury. That paper is still (as of late 2024) the most detailed treatment of factors causing susceptibility to acetaminophen-induced neurodevelopmental injury. This first review paper also introduced at least one new line of evidence, but it contains only 14 total lines of evidence. Not only do we now have many more lines of evidence, but the 14 lines of evidence presented in this paper are now much stronger. Therefore, this paper is not current in most respects.
In this first review, we conclude that “The bottom line is that hundreds of studies describing the epidemiology of autism and the numerous and varied risk factors for autism have a straightforward explanation: autism could be an acetaminophen-induced brain injury facilitated by oxidative stress and inflammation in newborns and young children. This is certainly an attractive view from an intellectual perspective, as it satisfies Occam’s razor.”
Published in 2022, five years after the first review, the second review takes an important step beyond the “could be” assertion made in the first review. In the second review, we conclude “without reasonable doubt” that exposure of susceptible children to acetaminophen is responsible for “many if not most” cases of autism spectrum disorder. That paper was published here https://pubmed.ncbi.nlm.nih.gov/35822581/. The paper contains a detailed analysis of laboratory animal studies, concluding that acetaminophen could never be used in babies and children, even on an experimental basis, if it had to pass current drug testing standards used by the FDA. However, that paper describes only 17 lines of evidence, and has been superseded by other papers described below which describe more lines of evidence.
The third review paper in the series was submitted for publication in October of 2022, but was not published until early in 2024. Sometimes publication of scientific papers can take considerable amounts of time. This paper described 20 lines of evidence demonstrating that exposure of susceptible babies and children causes many if not most cases of autism, and was published here: https://pubmed.ncbi.nlm.nih.gov/37321575/. It contains a detailed analysis of lines of evidence originating from the 2008 Schultz study parsing out the contribution of vaccines versus acetaminophen to autism. This third review paper is the only one that provides a detailed analysis of that evidence from Schultz. However, again, other papers have been published with additional evidence. In this case, the fourth review paper (see below), describing 22 lines of evidence, was published just a few days before this paper, meaning that this third review paper was outdated in some regards even before it was published. This situation is not unique in the field of science. Some papers get published faster than others, in this case due to differences in the time required for different scientific journals to publish the manuscript.
The fourth review paper in the series describes 22 lines of evidence demonstrating that exposure of children to acetaminophen is responsible for many if not most cases of autism https://pubmed.ncbi.nlm.nih.gov/38255358/. This fourth review is the first one in which we conclude that available evidence is consistent with the view that acetaminophen exposure in susceptible babies and children is responsible for “the vast majority” of all cases of autism. The paper was submitted for publication in November of 2023, and was published in December of the same year, shortly before the third review paper (described above) was published. Published in the journal “Children”, this fourth review paper is by far the most user-friendly paper on the topic we have published. It contains recommendations for medical practice, but of course does not contain medical advice for individuals. Only a medical doctor can provide medical advice for individuals.
Our fifth review paper on the topic described two new lines of evidence demonstrating the connection between acetaminophen and autism, bringing the total number of lines of evidence up to 24 https://pubmed.ncbi.nlm.nih.gov/39202661/. This paper contains a very detailed explanation of one new and important line of evidence: the similarities between autism spectrum disorder and fetal alcohol spectrum disorder. It also contains an analysis of historical evaluations of the prevalence of autism, which are important for two more lines of evidence related to temporal associations between acetaminophen use and autism. Finally, the paper contains a detailed proof of the fact that current studies related to two other lines of evidence have been grossly misguided. These two lines of evidence involve associations between autism and acetaminophen use during pregnancy (one line of evidence) and early childhood (another line of evidence) based on “observational” studies of healthcare databases. To summarize this paper, it contains a highly detailed scientific analysis of several lines of evidence, and it is the most current paper in the series, being based on 24 lines of evidence. However, this fifth paper does not contain a complete summary of all lines of evidence, and parts of it are not written to be digestible for the non-expert in statistical methods. Thus, the fourth review paper described above, published in Children, is still recommended as a general review for most people.
The bottom line is that it’s impossible to induce a neurodevelopmental injury in more than 2% of the population without leaving a trail of evidence. The evidence we have simply doesn’t fit into a single paper, and is spread out in reviews published over a period of 8 years. With that in mind, please be patient as you sort through the evidence, and let us know if you have questions.
24 Lines of Evidence
For your convenience, and in no particular order, we’ve put all lines of evidence with their references below. Some of the references point to review papers, which contain numerous additional references:
1 | Laboratory mice and rats develop long-term brain damage and exhibit behavioral changes following early life APAP exposure at doses that are similar to or even less than doses received by human babies and children | |
2 | In laboratory rats, APAP and related drugs affects the developing male brain more than the female brain | |
3 | APAP causes death of cortical neurons in adult laboratory rats at concentrations lower than it causes liver failure | |
4 | Despite the fact that APAP targets the brain, APAP use in babies and children was only proven safe for acute side effects, not for neurodevelopment | |
5 | Male circumcision, often performed using APAP as an analgesic, is associated with a dramatic increase in the risk for early-onset (infantile) ASD | |
6 | An unexpectedly high prevalence of ASD was identified in South Korea, where APAP-containing products for children were repeatedly found to contain amounts of drug exceeding the package label | |
7 | Ultra-Orthodox Jews and Arabs in Israel have a reported prevalence of ASD less than half of that of other Israelis. Israelis have high rates of circumcision concomitant with ritual use of alcohol. Alcohol use depletes glutathione, particularly in the brain, thereby increasing susceptibility to APAP-induced injury. Thus, use of traditional circumcision practices with alcohol but without APAP by some communities in Israel could account in part for their lower rates of ASD compared to other Israelis | |
8 | Analysis of 61,430 babies in the Danish National Birth Cohort found an odds ratio (OR) of 1.3 for ASD associated with postnatal APAP exposure. This result is especially concerning since heavy use of the drug among non-susceptible children will cause dramatic underestimation of the actual risk based on quantitative computer simulations. | |
9 | The ratio of regressive to infantile ASD rose at the same time as pediatric APAP use rose after aspirin was associated with Reye’s syndrome | |
10 | The incidence of ASD began to increase in the early 1980s, coinciding with the increase in APAP use after aspirin was associated with Reye’s syndrome | |
11 | The incidence of ASD has steadily increased as direct-to-consumer advertising and perhaps other factors have driven up use of pharmaceutical products | |
12 | Use of APAP in pregnant women is associated with long-term effects that include lower IQ, increased ASD, and ADHD. Prenatal use: Epidemiologic studies, some with controls for indication | |
13 | Levels of APAP in cord blood are associated with ASD | |
14 | APAP given alongside vaccine administration but not vaccination alone is associated with ASD | |
15 | Many parents believe that their children’s ASD was induced by a vaccine based on their own observations or the observations of trusted social networks. APAP is frequently used with vaccinations, although vaccinations alone do not cause ASD | |
16 | APAP use during early childhood is associated with a dramatic increase in regressive ASD | |
17 | APAP use in adults temporarily blunts social trust and awareness, emotional responses to external stimuli, and the ability to identify errors, indicating that the drug targets regions of the brain affected in patients with ASD | |
18 | Cystic fibrosis is associated with unusually efficient (effective) metabolism of APAP, which makes the drug much less toxic, and some evidence suggests that the prevalence of ASD may be very low in patients with cystic fibrosis | |
19 | Genetic and immune factors associated with an increased risk of ASD have a detrimental effect on the body’s ability to metabolize APAP, making the drug much more toxic. | |
20 | APAP is known to be highly toxic in the presence of oxidative stress. The mechanism by which this toxicity occurs has been established for decades, and involves the formation of the potent toxins, including NAPQI. More recent studies indicate that concomitant mitochondrial damage is important in the process | |
21 | Low doses of acetaminophen are lethal in cats because they are deficient in 'the glucuronidation pathway" of metabolism. This has been known for decades, but it was only recently recognized that this might be important for clinical practice: Newborn babies are also deficient in this metabolic pathway. | |
22 | During the 2006-2010 time frame, the sales of acetaminophen in Denmark were more than two fold greater than in Finland, and they had approximately 70% more autism than Finland. | |
23 | The absence of medication, including acetaminophen, in very low-income countries is associated with much less ASD compared to other mental health disorders such as Down syndrome. | |
24 | The similarities between ASD and FASD, including complex phenotypes and associations with multiple genetic and environmental factors, suggest that ASD, like FASD, is chemically induced. |