The influence of the Endocannabinoid System on Autism Spectrum Disorders

Autism is a developmental neurological condition present from childhood and permanent, which is usually characterized by difficulties in communication and social interaction. The term Autism Spectrum Disorder (ASD) is used to define a set of neuropsychiatric disorders of the child's development, resulting from dysfunctions in the development of the central nervous system. There are five types of disorders, but the main ones are classic autism, Asperger's syndrome, and Developmental Disorder Not Otherwise Specified. [1]

Autism Spectrum Disorders

According to the American Psychiatric Association, Autism Spectrum Disorder is “a neurobehavioral syndrome arising from central nervous system disorders that affect typical child development. Symptoms appear in the first three years of life and include three major domains of disturbance: social, behavioral, and communication” [2]

There is still no defined cause for autism and the current pharmacological treatment offers limited efficacy and serious side effects that compromise adherence to it.

The influence of the Endocannabinoid System on Autism Spectrum Disorders

In the last decade, several preclinical and clinical studies have been structured in order to analyze changes related to the modulation of the endocannabinoid system and administration of cannabinoids in patients with autism or generalized developmental disorders.

From these studies it was possible to conclude that:

1. Most drugs approved for the control of symptoms associated with ASD have low efficacy and a high risk of adverse effects. A literature review published in 2022 evaluated the effectiveness of new pharmacological agents for this purpose. Most of the randomized clinical trials performed (with fluoxetine and oxytocin, for example) had negative or inconclusive results. Two multicenter studies with bumetadine ended early due to lack of efficacy, with the only clinical trial that showed promising results for disruptive behaviors was carried out with cannabinoid-based drugs. [3]
2. The alterations associated with PEA are closely related to a generalized inflammatory state of the central nervous and immune system [4] as well as alterations major at the intestinal level [5,6] and the various components of the endocannabinoid system are present in high concentrations in the nervous system and gastrointestinal tract.

“The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders”

3. The administration of cannabinoid-based drugs was mostly able to reduce multiple symptoms, such as self-harm, hyperactivity, or sleep disturbances, for example, thus improving the quality of life of the patient and their care providers. The same studies reveal that cannabinoid treatment is a well-tolerated, safe, and effective option for alleviating symptoms associated with autism spectrum changes [7-9]

Based on the randomized, double-blind clinical trials conducted to date on this topic, we know that:

1. In 2021, Adi Aran and his team administered a chemotype III extract (CBD: THC – 20:1) to children with ASD with disruptive behaviors. In addition to being well tolerated, cannabinoid treatment demonstrated a significant 49% reduction in this type of behavior when compared to the placebo group. [10]
2. The striatum (caudate nucleus, whore and core accumbens) plays a crucial role during development and its atypical functional connectivity (FC) may contribute to the development of multiple symptoms associated with ASD. In 2021, Pretzsch C. et al demonstrated that administration of CBDV (cannabidivarin, 600 mg) modulated the atypical FC of individuals with ASD towards their typical neuro function [11]. In 2019, the same author reported changes related to cannabidiol (CBD) administration in the modulation of metabolites (GABA and glutamate) and regulation of the functional amplitude of low-frequency fluctuations (fALFF) and CF between regions consistently implicated in PEA [12,13, XNUMX].
3. In 2020, in Brazil, Estácio Amaro da Silva Júnior and colleagues concluded that the administration of a chemotype III extract improved the levels of anxiety, psychomotor agitation, social interaction and ability to concentrate in 30 children with ASD when compared to the placebo group. [14]
4. In 2018, in Iran, Mona Khalaj and colleagues suggested that administration of the endocannabinoid palmitoylethanolamide may synergize with risperidone in attenuating levels of hyperactivity and irritability associated with autism, through its ability to reduce inflammation and hyperstimulation of the glutamatergic system. . [15]

Finally, it is also important to mention that in 2021 the first observational study was developed, which aimed to determine the potential of pharmacometabolomics in the identification of metabolic biomarkers that respond to treatment with cannabinoids. Behavioral surveys were applied before the collection of 2 saliva samples (before and about 90 to 120 minutes after administration of cannabinoid-based drugs) to 9 healthy children and 15 children with autism (no history of epilepsy) under treatment with cannabinoids (THC – 0.05 to 50 mg and CBD – 7.5 to 200 mg).

Subsequently, changes in several biomarkers (N-acetyl-aspartate (NAA), Spermine, Cortisol, Dehydroepiandrosterone Sulfate and Glutamine, among others) were evaluated, which, according to the authors, after the administration of the morning dose of cannabinoid-based drugs , reached physiological levels identical to those of typically developing children.

“The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder.”

Published in the magazine Cannabis and Cannabinoid Research and conducted by Dr. Bonni Goldstein, a pediatrician from Los Angeles, with more than 13 years of clinical practice with cannabinoids, this study allowed the identification of the metabolic profile of children with ASD with a positive therapeutic response to treatment with cannabinoids. We can therefore consider Cannabis-Responsive™ biomarkers as a universal measure of analysis of the physiological impact of cannabinoid treatment, which provides healthcare professionals with objective and quantitative data, allowing them to customize and optimize cannabinoid treatment taking into account the profile of each individual. [16,17]

BIBLIOGRAPHY

[1] Portuguese Autism Federation – Accessed on July 28, 2022 at: https://www.fpda.pt/

[2] American Psychiatric Association (2013). Autism Spectrum Disorder - In Diagnostic and Statistical Manual of Mental Disorders (5th ed.)

[3] Baribeau, D., Vorstman, J. & Anagnostou, E. Novel treatments in autism spectrum disorder. Curr. opinion Psychiatry 35, 101–110 (2022). Doi: 10.1097/YCO.0000000000000775

[4] Siniscalco, D., Schultz, S., Brigida, A., and Antonucci, N. Inflammation and neuroimmune dysregulations in autism spectrum disorders.Pharmaceuticals 11, 56. (2018).  https://doi.org/10.3390/ph11020056

[5] McElhanon,BO,McCracken,C.,Karpen,S.,andSharp,WG Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-Analysis. Pediatrics 133 (5), 872–883.(2014). doi: 10.1542/peds.2013-3995

[6] Coccurello R, Marrone MC and Maccarrone M. The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders. Front Pharmacol. 13:869606. (2022) doi: 10.3389/ffhar.2022.869606

[7] Aran A, Cassuto H, Lubotzky A, et al. Brief report: Cannabidiol rich cannabis in children with autism spectrum disorder and severe behavioral problems – A retrospective feasibility study. J Autism Dev Disorder 49: 1284–1288. (2018) doi:10.1007/s10803-018-3808-2

[8] Bar-Lev Schleider, L., Mechoulam, R., Saban, N., Meiri, G., and Novack, V. Real Life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Sci. Rep. 9, 200. (2019). doi:10.1038/S41598-018- 37570-Y

[9] Fleury-Teixeira, P., Caixeta, FV, Ramires da Silva, LC, and Brasil-Neto, R. Effects of Cbd-Enriched Cannabis Sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use. Front Neurol. 10. (2019). doi: 10.3389/fneur.2019.01145

[10] Aran et al. Cannabinoid treatment for autism: a proof-of-concept randomized trial. Mol. autism (2021) 12:6. https://doi.org/10.1186/s13229-021-00420-2

[11] Pretzsch, Charlotte M., Floris, Dorothea L., Voinescu, Bogdan, Elsahib, Malka, Mendez, Maria A., Wichers, Robert, Ajram, Laura, et al., Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin. Mol. autism 12 (1). (2021)  https://doi.org/10.1186/s13229-021-00454-6.

[12] Pretzsch CM, Voinescu B, Mendez MA, Wichers R, Ajram L, Ivin G, et al. The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD). J Psychopharmacol. 2019;33:1141–8. (2019) https://doi.org/10.1177/0269881119858306

[13] Pretzsch CM, Freyberg J, Voinescu B, Lythgoe D, Horder J, Mendez MA, et al. Effects of cannabidiol on brain excitation and inhibition systems; a randomized placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology.;44(8):1398–405. (2019); https://doi.org/10.1038/s41386-019-0333-8

[14] Junior E. et al. Evaluation of the efficacy and safety of cannabidiol-rich cannabis extract in children with autism spectrum disorder: randomized, double-blind and controlled placebo clinical trial. Trends Psychiatry Psychother – Journal Article Pre-Proof (2020) http://dx.doi.org/10.47626/2237-6089-2021-0396

[15] Khalaj M, Saghazadeh A, Shirazi E, Shalbafan MR, Alavi K, Shooshtari MH, et al. Palmitoylethanolamide as Adjunctive Therapy for Autism: Efficacy and Safety Results from a Randomized Controlled Trial. J. Psychiatr. Res. 103, 104–111. (2018) https://doi.org/10.1016/j.jpsychires.2018.04.022

[16] Siani-Rose M., Cox S., Goldstein B., Abrams D., Taylor M., Kurek I Cannabis-Responsive Biomarkers: A Pharmacometabolomics-Based Application to Evaluate the Impact of Medical Cannabis Treatment on Children with Autism Spectrum Disorder. Cannabis and Cannabinoid Research X:X, 1-12, (2021) DOI: 10.1089/can.2021.0129

[16] Siani-Rose M., McKee R., Cox S., Goldstein B., Abrams D., Taylor M., Kurek I. The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder. Cannabis and Cannabinoid Research X:X, 1-15 (2022) DOI: 10.1089/can.2021.0224.

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* Soraia Tomás is a Nurse, graduated from the Escola Superior de Enfermagem de Coimbra in 2015. She worked in the intensive care of Cardio-Thoracic surgery and lung transplantation in Lisbon. She currently works at the Spine Center, a spine surgery service and an intensive care unit for general surgery at Hospital da Luz in Coimbra, the city where she lives. Enthusiastic in the field of Medicinal Cannabis, he is a member of the scientific council of the Portuguese Observatory of Medicinal Cannabis, attended conferences in this area (Portugal Medical Cannabis, Cannabis Europa, CannX, among others) and obtained a postgraduate degree in GMP's for Medicinal Cannabis, course carried out by the Portuguese Observatory of Medicinal Cannabis in partnership with the Military Laboratory of Chemical and Pharmaceutical Products and the Faculty of Pharmacy of the University of Lisbon. President of the Board of APCNNA – Portuguese Association for Information on Cannabis, intends to develop projects dedicated to the dissemination, education and training in medical cannabis to health professionals and the general public, thus promoting excellence in professional practice and safe and effective access to cannabinoid therapies.