Autism spectrum disorders (ASDs) are characterized by difficulty with social interaction, repetitive behaviour and limited empathy with peers. Some forms of autism also lead to cognitive and linguistic impairment, although Asperger’s syndrome is an exception to this. So what role does the endocannabinoid system have to play?
The EC system is fundamentally linked to autism spectrum disorders
In recent years, a significant body of research has accumulated exploring the link between the endocannabinoid system and ASDs. It has been demonstrated that CB1-receptors are most concentrated in areas in the brain thought to be dysfunctional in cases of autism, namely the cerebellum, hippocampus, and the basal ganglia (Bauman and Kemper 2005, Courchesne et al. 2007).
As the human foetus develops, CB1-receptors and their associated endocannabinoids play an integral role in neuron differentiation and axonal migration (Fride et al. 2009), processes that are essential for normal neurological development. Furthermore, recent studies suggest that CB1-receptors are responsible for defining the positioning of the synapses themselves (Harkany et al. 2008). It is therefore suggested that activation of CB1-receptors in infancy could trigger ASDs by interrupting normal brain development.
The role of the CB2-receptors in ASDs
The CB2-receptors also have a possible role to play in autism, however. It has been shown that CB2-receptor agonists decrease the rate at which certain important immune cells known as monocytes migrate across the endothelium—the thin layer of cells that separate the circulatory system from the tissues and organs (Rajesh et al.2007). Monocytes are one of the key cell types related to the immune system, and disruption to their deveopment and function has been implicated in the development of ASDs on several occasions (Jyonouchi et al. 2014, Entstrom et al. 2010).
A recent study (Siniscalo et al. 2013) demonstrated that in children with autism, levels of CB2-receptors in the monocytes were increased, while levels of CB1-receptors and the anandamide-degrading molecule fatty acid amide hydrolase (FAAH) were unchanged.
The role of acetaminophen/paracetamol in the development of autism
There is evidence to suggest that ASDs could actually be triggered in children by use of paracetamol (acetaminophen), which is believed to exert its analgesic effects by acting on the cannabinoid receptors.
Acetaminophen is deacetylated in the central nervous system to the compound p-aminophenol, which in turn reacts with arachidonic acid (catalysed by FAAH). This reaction produces the compound N-arachidonoylphenolamine (AM404), which inhibits the cellular uptake of anandamide. As a result, anandamide levels increase and produce an analgesic effect.
Furthermore, it has been shown that blocking the CB1-receptors with antagonists completely prevents the analgesic effect of acetaminophen. Thus, it is now known that acetaminophen exerts its effects through degradation to AM404 and activation of the CB1-receptors, although at least one study has indicated that AM404 exerts its effects via the CB1, CB2, and TRPV1 receptors together.
It has been suggested that use of acetaminophen in early childhood may lead to the development of autism by disrupting normal immunological development (Torres 2003). Children who are less able to metabolize acetaminophen may therefore be at increased risk of developing autism, as higher levels of the compound will remain present in the blood for longer periods.
Could the MMR controversy actually be related to paracetamol use?
Indeed, there is substantial evidence indicating that children experiencing fever exhibit fewer and less severe symptoms of autism than in normal times (Curran et al.2007). Furthermore, activation of the CB1-receptors causes a decrease in body temperature, as well as providing an analgesic effect (Fraga et al. 2009).
Interestingly, as the MMR vaccine is known to cause mild fever in some children it is administered to, it has been suggested (Schutlz 2010) that a trigger for the development of autism is in fact the acetaminophen commonly used to treat the fever symptoms, rather than the vaccine itself. Indeed, experiencing fever may be useful to the normal immunological development of a child, and disrupting this process with CB1-receptor agonists may prove to increase the risk of autism developing. However, this hypothesis has not been tested to date.
The possible role of the dopamine signalling system in ASDs
One case study (Dratcu et al. 2007) reports the story of a middle-aged man previously been diagnosed with schizophrenia due to his psychotic symptoms being admitted to an acute psychiatric unit, where for the first time in his life a diagnosis of Asperger’s syndrome was pronounced. Schizophrenia and Asperger’s have many features in common, and the two are often confused due to this.
After treatment with the antipsychotic drug aripiprazole, the symptoms of Asperger’s significantly improved. Aripiprazole is a partial agonist at the dopamine D2-receptors, and there is substantial evidence to demonstrate that both schizophrenia and Asperger’s fundamentally involve dopamine dysfunction.
It appears that anandamide may have a part to play in this process. Anandamide is known to play a role in dopaminergic signalling, although the exact mechanism has not been precisely elucidated; however, existing studies (listed in the extensive review, Beltramo et al.2000) indicate that one of the many functions of anandamide within the CNS may be to modulate psychomotor and social activity primary facilitated by the dopamine D2-receptor.
What part does genetics have to play in the development of ASDs?
It was previously believed that the proportion of autism cases attributable to genetic factors was as high as 90%. It is now thought that this was an overestimate due to poorly-designed twin studies, and that the actual heritability of autism is around 30%.
One form of autism, fragile-X sydrome, is the most common monogenic (i.e. caused by a mutation to a single gene or chromosome) cause of inherited autism, and is caused by the inactivation of the FMR1 gene, which is responsible for the production of the FMR protein. It it well-known that the endocannabinoid system is implicated in the regulation of cognitive function, anxiety, perception of pain, susceptibility to seizures, and synaptic plasticity (the ability for synapses to strengthen or weaken depending on their level of activity), all of which are affected in fragile-X.
A study (Busquets-Garcia et al. 2013) investigating the role of the EC system in male mice bred to lack the FMR1 gene found that blocking the CB1-receptors normalized cognitive damage, sensitivity to pain, and susceptibility to seizures, while blocking the CB2-receptors normalized anxiety levels.
So how could ASDs be helped by this?
In recent weeks, much has been made of the recent decision by the Michigan Medical Marijuana Review panel to approve the use of cannabis for ASDs—although the final decision now lies with the Department of Licensing and Regulatory Affairs, which must issue its judgment by late October.
There are various anecdotal examples of children whose autism symptoms are improved with use of medical cannabis—for example, a 9-year-old, severely-autistic boy named Kalel Santiago was recently reported to have spoken his first words after treatment with CBD-rich hemp extract. Just as with epilepsy, it appears that the majority of parents administering cannabis to their autistic children are utilizing CBD-rich oils, apparently with positive results. If activation of the cannabinoid receptors during the child’s development is an underlying cause of ASDs, it stands to reason that administration of antagonists such as CBD would negate this effect.
However, there is also at least one report of autistic children experiencing more significant relief from symptoms when using THC and CBD together. From the existing reports, children who appear to benefit from higher THC ratios are those who suffer from both epilepsy and ASD. There is also one case study of a six-year-old autistic boy whose symptoms were markedly improved by treatment with the synthetic THC analogue dronabinol.
It is important to stress that these are anecdotal results not borne out by rigorous empirical testing to ensure that no other factors are responsible for the apparent effect, and thus it is insufficient for most doctors to comfortably recommend THC-rich medical cannabis products to children, particularly when concerns remain over the effect of THC on the developing brain. Furthermore, the various different types of autism may respond differently to administration of THC, and more research is required to determine exactly what those responses could be.
As research into this particular area of neuroscience intensifies, we will no doubt see the development of targeted therapies to treat the symptoms of ASD in developing children, in an attempt to prevent the disease from intensifying in severity and possibly even to reverse existing neurological damage; it is also likely that we will be able to develop targeted therapies allowing adults diagnosed with ASD to live normal or at least greatly improved lives.
Author: Seshata @ Sensiseeds