Part One: The Endocannabinoid System and Autism Spectrum Disorder (ASD)

The importance of the discovery of the role that the endocannabinoid system (ECS) plays in human health and disease cannot be understated. Cannabinoid receptors are the most highly expressed of any G-protein coupled receptor (GPCR) in the body. They’re the only ones to play a direct role in virtually every aspect of the human body (CNS and immune systems, throughout the periphery, presynaptic, and postsynaptic).It’s no wonder that anecdotal reports of cannabis treatments indicate effectiveness in such a wide array of conditions. The growing body of scientific research surrounding the endocannabinoid system continues to lead to the further understanding of the physiological basis in a growing number of conditions.One condition with both supportive anecdotal and preclinical scientific evidence is for patients on the severe end of the autism spectrum (ASD). 

NL3 Mutations Inhibit Tonic Endocannabinoid Secretions

Neuroligins are part of a family of neuronal cell surface proteins that “connect presynaptic and postsynaptic neurons at synapses, mediate signaling across the synapse, and shape the properties of neural networks by specifying synaptic functions”. Alterations in genes encoding neuroligins are associated with autism and other cognitive diseases.

Mutations in neuroligin-3 (NL3), a member of the family of neuroligins, are associated with ASD. NL3 is required for tonic secretion of endocannabinoids (AEA, 2-AG). NL3 mutations have been shown to inhibit tonic endocannabinoid secretion. This dysregulation in endocannabinoid signaling may contribute to the pathophysiology of autism. These findings have in part prompted researchers to apply to conduct research with nonhuman primates in order to further elucidate this association.

Targeting Endocannabinoid System to Treat FXS

Fragile X syndrome (FXS) is the most commonly known genetic cause of autism. FXS is associated with a loss of the fragile X mental retardation protein (FMRP) which regulates signal transduction in the brain. This FMRP deficiency is believed to “increase neuronal excitability which is mediated by endocannabinoids”.

FXS is also associated with “neuropsychiatric problems such as hyperactivity, attention disorders, and seizures.” The endocannabinoid system is key to modulating functions that are involved with regulating all of these disorders including “synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility.” The endocannabinoid system is specifically implicated in just about all aspects of FXS including “behavioral, synaptic and molecular manifestations.”Preclinical research implicates CB1 and CB2 as pharmacological targets with the potential to reduce cognitive deficits and anxiety in FXS models in rodents.

Increased Expression of CB2 Receptors Associated with ASD

Though it wasn’t long ago that the role that CB2 receptors played in the human brain was believed to be negligible, additional research has implicated it as having a much more substantial role than previously understood.

“Given that CB2 is up-regulated, and that it’s believed to play a neuroprotective role, CB2 is being investigated as a potential target for treatment of ASD.”

One example is that CB2 is believed to play a neuroprotective role in response to a variety of inflammatory stimuli, this has implications in a number of neuropsychiatric conditions including ASD.

In ASD, as well as a number of conditions, the expression level of CB2 receptors increases in response to the inflammatory nature of the condition. Given that CB2 is up-regulated, and that it’s believed to play a neuroprotective role, CB2 is being investigated as a potential target for treatment of ASD.

Elevated Cytokine Levels Associated with ASD

“Cytokines are small secreted proteins released by cells that have a specific effect on the interactions and communications between cells… Pro-inflammatory cytokines are involved in the up-regulation of inflammatory reactions.”

Elevated pro-inflammatory cytokine levels are associated with ASD. Whether this is due in part as a result of NL3 mutations inhibiting tonic secretion of endocannabinoids remains uncertain. However, endocannabinoids (AEA, 2-AG) have been shown to play key roles inhibiting cytokines via CB2.

The majority of cannabinoids have been demonstrated to decrease cytokine production via CB1/CB2 dependent and independent mechanisms.

Clinically Diagnosing ASD via the ECS

A team of researchers recently discovered and patented a process that claims that it’s possible to clinically diagnose ASD, and susceptibility to it, via observation of the degree of modulation that acetaminophen has on endocannabinoid levels. However, based on a series of deductions made within their published literature, it appears that additional research is required.

Other Relevant ECS/ASD Implications

The number of functions that ECS regulate is extensive and beyond the scope of this paper. However, a few potentially relevant aspects to ASD will be listed:

• “CB1 variations modulate the striatal function that underlies the perception of signals of social reward, such as happy faces. This suggests that CB1 is a key element in the molecular architecture of perception of certain basic emotions. This may have implications for understanding neurodevelopmental conditions marked by atypical eye contact and facial emotion processing, such as ASC.”
• “Endocannabinoids are key modulators of synaptic function.”
• Tonic secretions of endocannabinoids regulate GI functions (including metabolism).
• Endocannabinoids regulate stress responses, in part via the modulation of the 5-HT system.
• Additional targets of endocannabinoids (and exogenous cannabinoids), PPARα, PPARγ, and GPR55 expression levels have shown reductions in a valproic acid model of autism in rats.

Conclusion

Based on the preclinical research the endocannabinoid system appears to be directly impacted by, as well as a potential target for treatment of, physiological manifestations of genetic factors associated with ASD including NL3 mutations and FXS. NL3 mutations inhibit tonic secretion of endocannabinoids and disrupt their signaling. This possibly contributes to the identified increase in pro-inflammatory cytokines levels in ASD. CB2 is upregulated in the brain in response to inflammatory stimuli as part of a neuroprotective role, and is suggested as a target for treatment. There appears to be a preponderance of evidence that the ECS is involved in the progression of ASD.

Explore the similarities between phytocannabinoids and endocannabinoids, as well as any potential practical applications cannabinoids might provide for treatment of ASD in the next article in this series.