Understanding how acetaminophen can damage the developing brain is the next step when moving from association to causation. This is referred to as "Biological Plausibility." In this 2021 study from the University of Texas, researchers explain how acetaminophen interacts with the endocannabinoid system in the brain to provide its pain-reducing analgesic effects. Reductions in compounds produced by the endocannabinoid system have been found in children with autism spectrum disorder (ASD). This abnormality is of great concern as endocannabinoid compounds are needed for proper synaptogenesis (connections between brain cells), axon growth and positioning (size and where these brain cells are located), and neuronal cell fate (whether a neuron lives or dies in a process known as apoptosis). With this understanding, it is of great concern that the studies investigating acetaminophen show the drug can alter and reduce the endocannabinoid system in the brain. thereby providing a plausible explanation for decreased brain development.
AUTHORS STATEMENT BELOW
We have reviewed the link between the endocannabinoid system and ASD [8]. As shown in Figure 1 from our 2013 paper, the ECS consists of the classical cannabinoid receptors 1 and 2 (CB1 and CB2) along with the endocannabinoids that activate them, primarily anandamide and 2-arachidonylglycerol (2-AG), and the enzymes responsible for their synthesis and degradation. Diacylglycerol lipase (DAG lipase) is responsible for the synthesis of 2-AG, and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) is the key enzyme for the synthesis of anandamide. The enzyme responsible for 2-AG degradation is monoacylglycerol lipase (MAGL), and the enzyme that degrades anandamide is fatty acid amide hydrolase (FAAH). The endocannabinoid receptors regulate cells by reducing the activation of adenylyl cyclase, thereby decreasing the production of cyclic adenosine monophosphate (cAMP). The ECS provides regulation for the immune system through CB2 receptors on immune system cells. CB1 receptors are found atthe highest concentration in the brain and the peripheral nervous systems, where they provide a regulatory function that is required for proper synaptogenesis, axon growth and positioning, and neuronal cell fate [9]. The lack of proper control over axon growth could result in improper development of the corpus callosum, which provides a pathway for axons traversing the brain from one hemisphere to the other.
Acetaminophen is a commonly administered analgesic drug, and research has indicated that its use in children may increase the risk for autism. This risk may be due to a decrease in endocannabinoid tone in the brain. It may be possible to increase this tone through use of cannabinoids, such as CBD and CBDV, in order to increase endocannabinoid activity in the brain.
We have also shown that the MMR vaccine along with acetaminophen use may indirectly increase the risk for ASD [3]. This may be because acetaminophen use disrupts the normal functioning of the ECS to fight infection from the three vaccine viruses in the MMR vaccine. This would keep inflammatory cytokines at high levels in the brain and could disrupt the normal growth and myelinization of axons for neurons in the brain. We have reviewed the increase in inflammatory cytokines in the brain of individuals with ASD.
n summary, evidence for the association of acetaminophen use with increased risk of ASD has been presented. In ASD children, abnormal functioning of the ECS may be the result of acetaminophen use. Further research needs to be performed to evaluate if CBD, CBDV, or other cannabinoids, will be effective treatments for ASD.