Endocannabinoid System (ECS) Dysregulation May Underlie Autism

Characterization of Autism Spectrum Disorder (ASD)

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder whose description has expanded over time to include a broad spectrum of mild to severe disorders. ASD is generally described as being a group of neurological conditions characterized by a combination of difficulties with social communication and difficulties with behavior, including the presence of repetitive patterns of behavior (1–3).

There are many comorbidities commonly linked to ASD. Some of the commonly noted ones include (1–3):

• Seizures
• Anxiety
• Depression and other mood disorders
• Learning and memory problems
• Intellectual disabilities
• Motor dysfunctions
• Sleep disturbances
• Metabolic disorders
• Immune system disorders

ASD is generally diagnosed in children, it’s more common in boys than in girls, and its prevalence in the US has been increasing over time, from 1 in 150 children in 2000 (6.7 per 1000) to 1 in 36 children in 2020 (27.8 per 1000) (see Figure 1) (4).

Endocannabinoid System (ECS) Dysfunction in ASD Patients

The defining characteristics of people with ASD, together with the vast majority of more common comorbidities, all fall within the realm of activities primarily governed by the endocannabinoid system (ECS). In other words, ASD may actually result from ECS dysfunction. In this case, ASD could be classified as being due to a clinical endocannabinoid deficiency, hypothesized by Ethan Russo to underlie several treatment-resistant conditions, including migraine, fibromyalgia, and irritable bowel syndrome, all of which have been linked to ASD (5).

Social Behaviors

The first diagnostic criterion for autism is “persistent deficits in social communication and social interaction across multiple contexts,” where the specific examples provided all basically encompass problems with social reward processing (6). People are social animals, which makes their ability to interact well with others critical for being able to establish relationships. The problems that people with ASD have with social reward processing, which inhibits the ability of ASD patients to maintain good relationships with others, is thus devastating.

Studies on both animals and humans suggest that many of the social behavior problems that people with ASD experience may be caused by dysfunctions in the ECS. For example, human neuroimaging studies indicate that areas of dysfunction in people with autism include the cerebellum, the hippocampus, and the basal ganglia. Studies also show that CB1 receptors are concentrated in these areas of the brain and are responsible for moderating social reward processing. Finally, postmortem studies of brains in people with ASD indicate they have reduced CB1 receptor expression in these areas (1). Taken together, this all suggests that low CB1 tone may contribute to problems that people with ASD experience regarding deficits in social reward response.

Furthermore, relative to healthy children, children with ASD have been shown to have lower plasma levels of the endogenous cannabinoid anandamide (AEA) (1,2). Animal studies suggest that higher AEA and tetrahyrdrocannabinol (THC) levels are each associated with increases in social play behavior (2). Taken together, this suggests that low levels of cannabinoids in people with ASD may be impairing their tendency to engage with others.

Repetitive Behaviors

The other major diagnostic criterion for autism is “restricted, repetitive patterns of behavior, interests, or activities” (6).

As just noted, children with ASD have been shown to have lower levels of AEA. Animal studies suggest that higher AEA levels at CB1 receptors decrease locomotor movement, which suggests the ECS moderates repetitive behaviors (2). That is, low levels of cannabinoids in people with ASD may contribute to repetitive behaviors in these patients.

At the same time, overactive microglial (immune system) cells may also be linked to repetitive behaviors in patients with ASD (7). Since the ECS moderates immune system activity (2,3), this is another mechanism by which dysregulation in the ECS may contribute to repetitive behaviors in patients with ASD.

From yet another angle, as noted above, CB1 receptors in the cerebellum, hippocampus, and the basal ganglia are found to be at lower levels in ASD patients. The cerebellum plays a significant role in repetitive behaviors (8), suggesting that low CB1 tone in the cerebellum of ASD patients may also contribute to this problem.

Learning and Memory

Problems with learning and memory are often cited as ASD comorbidities.

Synaptic plasticity is activity-dependent change in the strength of connections between neurons, which is generally accepted to play an important role in learning and memory (9). Animal studies have linked ASD to synaptic plasticity dysfunction (1,2). The ECS has been shown to modulate synaptic plasticity through its role in regulating melatonin (10). These two findings suggest that learning and memory problems in ASD may thus be due to ECS-driven dysfunction in synaptic plasticity (2,3).

As noted above, CB1 receptors in the cerebellum, hippocampus, and the basal ganglia are found to be at lower levels in ASD patients. Animal studies have shown that CB1 receptor stimulation increases the spatial memory performance (2). This further suggests that memory problems in ASD may be due to ECS-driven dysfunction.

Coming at the issue of learning and memory from yet another angle, social rewards processing is “crucial for learning and adaptive behavior” in situations involving social interaction (11). As previously discussed, ECS dysfunction may contribute to problems people with ASD have with social rewards processing and thus, perhaps, learning.

Immune System Disorders

A variety of ASD comorbidities are linked to dysregulation of the immune system, including chronic inflammation, gastrointestinal (GI) problems, autoimmune diseases, and mental health issues (12).

Patients with ASD have been found to have abnormal immune system activity, where greater levels of abnormality have been associated with more severe forms of ASD (2). The ECS is intimately involved with immune system activity, that is, CB2 receptors moderate immune system activation, which causes immune dysfunction, increased autoimmune activity and inflammatory responses in patients with ASD (2,3). Furthermore, significantly altered levels of ECS activity (CB2 receptors and ECS enzymes) were found in animal models of ASD (2) and in blood cells of ASD patients (3). Taken together, the evidence suggests that ECS dysfunction may drive immune system disorders in patients with ASD.

ECS Dysfunction in Comorbidities of ASD Patients

Researchers have established clear mechanisms of action by which the ECS regulates many of the comorbidities experienced by ASD patients.

Seizures

Researchers estimate that about 20–25% of people with ASD have epilepsy (13). Babayeva and colleagues noted (2) that “cannabis, cannabinoids, and endocannabinoids have been extensively studied and found to have antiseizure activities.” This suggests ECS dysfunction may underlie seizure disorders in patients with ASD.

Anxiety and Other Mood Disorders

ASD patients have a high incidence of anxiety, depression, bipolar disorder, and other mood disorders, perhaps associated with their difficulties with communication, social interaction, sleep, and so forth. As with seizures, there is deep literature establishing a link between the ECS and mood (1–3). This suggests ECS dysfunction may underlie mood disorders in patients with ASD.

Sleep

People with ASD tend to have problems falling asleep and staying asleep that can exacerbate repetitive behaviors, which can, in turn, make sleep more difficult (14). The ECS has been shown to modulate circadian rhythms through its role in regulating melatonin (10). This suggests ECS dysfunction may underlie sleep disorders in patients with ASD.

Cannabis Addresses ASD Symptoms

Studies of cannabis use in animals and in people with ASD have shown that cannabis may be effective in addressing many ASD symptoms.

CBD Improves Symptoms of ASD

In Mice Models of ASD, CBD Increases AEA Levels

In mice models of ASD, cannabidiol (CBD) increased the serum levels of AEA by inhibiting its breakdown (2), presumably responsible for improvements seen in social and compulsive behaviors in mice (2).

In Mice Models of ASD, CBD Modulates Immune System Activity

In mice models of ASD, CBD decreased immune system activity and decreased inflammation, presumably responsible for reducing anxiety- and depression-like behavior, poor social interaction, and increased rearing behavior, as well as reference memory and working memory in mice (2).

In Clinical Studies of ASD Patients, CBD Improves Symptoms of ASD

A study of 53 children and young adults with ASD showed that CBD improved self-injury and rage attacks, hyperactivity symptoms, sleep problems, and anxiety (15). A study of 60 children with ASD showed that CBD improved behavioral outbreaks, communication problems, anxiety, stress, and disruptive behavior (16).

CBD and THC Improve Symptoms of ASD

A study of 188 ASD patients using 30% CBD:1.5% THC oil showed moderate to significant improvements in quality of life, mood, and ability to perform activities of daily living (16). A study of 82 ASD patients using a 20:1 CBD:THC extract showed improvements in social communication skills (17).

THC Improves Symptoms of ASD

In Mice Models of ASD, THC Improves Symptoms of ASD

In a mouse model of ASD, THC increased locomotor behavior and reduced depression (2). In another mouse model of ASD, a synthetic CB1 receptor agonist reduced aggressive behavior (15).

In Clinical Studies of ASD Patients, THC Improves Symptoms of ASD

A case study showed THC (Dronabinol) improved hyperactivity, lethargy, irritability, stereotypy, and inappropriate speech (16). A study of 10 adolescent patients showed THC (Dronabinol) helped with self-injurious behavior (16).

Conclusion

In sum, both the defining characteristics of ASD and most of its common comorbidities fall within the realm of activities primarily governed by the ECS. It follows that the underlying cause of ASD may be ECS dysfunction, that is, ASD could be classified as being due to a clinical endocannabinoid deficiency.

References

1. Zamberletti, E. et al The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models. Molecular Sciences. (2017, Sep). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618565/pdf/ijms-18-01916.pdf
2. Babayeva, M. et al, Autism and associated disorders: cannabis as a potential therapy. Front. Biosci. (2022). https://www.imrpress.com/journal/FBE/14/1/10.31083/j.fbe1401001
3. Brigida, A.L. et al, Endocannabinoid Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations. International Journal of Molecular Sciences. (2017, Jul 3). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535916/pdf/ijms-18-01425.pdf
4. Data & Statistics on Autism Spectrum Disorder. CDC. https://www.cdc.gov/ncbddd/autism/data.html
5. Russo, E., Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions? Neuroendocrinology Letters. (2004, Feb 2). http://ethanrusso.org/wp-content/uploads/2020/02/Russo-Clinical-Endocannabinoid-Deficiency-NEL-2004.pdf
6. Autism Diagnosis Criteria: DSM-5. Autism Speaks. https://www.autismspeaks.org/autism-diagnosis-criteria-dsm-5
7. Su, T., et al, Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia. Frontiers in Psychiatry. (2021, Oct 22). https://www.frontiersin.org/articles/10.3389/fpsyt.2021.734837/full
8. Dean, S. et al, The Role of the Cerebellum in Repetitive Behavior Across Species: Childhood Stereotypies and Deer Mice. The Cerebellum. (2021, Aug 14). https://link.springer.com/article/10.1007/s12311-021-01301-3
9. Magee, J. and Grienberger, C., Synaptic Plasticity Forms and Functions. Annu Rev Neurosci. (2020). https://pubmed.ncbi.nlm.nih.gov/32075520/
10. Rossignol, D. and Frye, R. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology. (2011). https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1469-8749.2011.03980.x
11. Martins, D. et al, Mapping social reward and punishment processing in the human brain: A voxel-based meta-analysis of neuroimaging findings using the social incentive delay task. Neuroscience and Biobehavioral Reviews. (2021). https://www.sciencedirect.com/science/article/abs/pii/S0149763421000026
12. Immune Function in Autism. Autism Research Institute. https://autism.org/immune-function-in-autism/
13. Mostafavi, M. and Gaitanis, J. Autism Spectrum Disorder and Medical Cannabis: Review & Clinical Experience. Seminars in Pediatric Neurology. (2020). https://pubmed.ncbi.nlm.nih.gov/32892960/
14. Furfaro, H. Sleep problems in autism, explained. Spectrum. (2020, Feb 6). https://www.spectrumnews.org/news/sleep-problems-autism-explained/
15. Schultz, S. and Siniscalco, D., Endocannabinoid system involvement in autism spectrum disorder: An overview with potential therapeutic applications. Molecular Science 2019, May 13). https://www.aimspress.com/fileOther/PDF/Molecular/molsci-06-01-027.pdf
16. Bar-Lev Schleider, L. et al, Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Scientific Reports. (2019, Jan 17). https://www.nature.com/articles/s41598-018–37570-y
17. Hacohen, M. et al, Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study. Translational Psychiatry. (2022). https://www.nature.com/articles/s41398-022-02104-8

About the Author

Ruth Fisher, PhD, is a systems design researcher and analyst. She analyzes markets to determine how environments shape outcomes. She is co-founder of CannDynamics, and author of The Medical Cannabis Primer and Winning the Hardware-Software Game: Using Game Theory to Optimize the Pace of New Technology Adoption. Dr. Fisher has worked in the technology and healthcare sectors on behalf of technology companies, early-stage researchers, physicians, and technology start-ups.