What is it?

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that poses significant challenges in understanding its underlying causes and developing effective treatments. The heterogeneity of ASD and its varied presentation among individuals necessitate innovative approaches to therapy. In recent years, research has turned to the endocannabinoid system (ECS) and the potential of cannabinoid therapy, particularly with cannabidiol (CBD), as a novel avenue for addressing the core symptoms and associated comorbidities of ASD.

• 61 Primary Studies
• 1 Clinical Meta-analyses
• 9 Double-blind human trials
• 6 Clinical human trials
• 36 Meta-analyses/Reviews 
• 8 Animal studies
• 1 Laboratory studies

The Endocannabinoid System and ASD

The ECS, a signaling system composed of endogenous cannabinoids and their receptors, plays a crucial role in maintaining homeostasis within the body. Recent studies have highlighted ECS dysregulation in individuals with ASD. Notably, children with autism exhibit lower blood levels of anandamide (AEA), an endocannabinoid that influences mood, pain perception, and social behavior. This suggests a potential link between ECS dysfunction and the social communication and interaction deficits observed in ASD.

Modulating Neurobiology for Therapeutic Benefits

Research has demonstrated that the ECS plays a multifaceted role in ASD’s neurobiology. Modulation of the ECS can impact neurotransmitter systems, such as monoaminergic and oxytocin systems, which are pivotal for social functioning. Moreover, ECS involvement in processes like neuroinflammation, neurogenesis, and cognitive function hints at its potential therapeutic value for ASD treatment.

CBD’s Promise in ASD Treatment

Cannabidiol, a non-psychoactive component of cannabis, has garnered significant attention for its therapeutic potential in various medical conditions, including epilepsy and anxiety disorders. Studies have shown that CBD can modulate the ECS, promoting a state of balance and potentially addressing ECS dysregulation observed in ASD.

The safety and tolerability of CBD have been well-established, providing reassurance for its potential use in ASD treatment. Reports highlight CBD’s anticonvulsant, anxiolytic, and anti-inflammatory properties, offering a multi-pronged approach to addressing the complex symptoms of ASD. Furthermore, CBD’s ability to mitigate common comorbidities, alongside core symptoms, underscores its potential to enhance the overall quality of life for individuals with ASD.

Bridging the Gap: Challenges and Future Directions

While the preliminary findings are promising, it’s crucial to emphasize the need for further research before cannabinoid therapy becomes a standard treatment for ASD. Rigorous clinical trials involving larger and more homogeneous samples are necessary to validate the effectiveness of CBD in diverse ASD populations. Long-term studies will shed light on the sustainability of CBD’s benefits and potential interactions with other treatments.

Cannabinoid-Responsive Biomarkers as Indicators of Treatment Efficacy

Recent research has explored the use of cannabinoid-responsive biomarkers to gauge the impact of medical cannabis treatment on children with ASD. Salivary lipid-based biomarkers and metabolic indicators have emerged as potential tools for evaluating treatment outcomes. These biomarkers not only provide insights into the physiological changes induced by cannabinoid therapy but also offer a means to objectively assess improvements in behavioral aspects, such as social interaction preference.

Endocannabinoid Modulation of ASD-like Traits

A 2023 study published in Nature explored the distinct effects of anandamide and 2-arachidonoylglycerol (2-AG) on autistic-like traits within a genetic rat model of autism. aiming to elucidate the role of endocannabinoid neurotransmission in these traits. Fmr1-Δexon 8 rats, a validated model of autism, exhibited reduced anandamide levels in the hippocampus and heightened 2-AG content in the amygdala. Intriguingly, manipulating endocannabinoid tone led to significant outcomes. Boosting anandamide levels ameliorated cognitive deficits while blocking 2-AG signaling in the amygdala mitigated altered sociability. These findings, observed in a brain region-specific manner, highlight the nuanced impact of endocannabinoid mechanisms on ASD-related behavioral phenotypes. While mechanisms behind cannabinoid compound benefits in neurodevelopmental disorders remain largely uncharted, this study contributes critical insights to this evolving field.

Cannabinoid treatment for autism: a proof-of-concept randomized trial

In a randomized trial involving 150 individuals (ages 5-21) with ASD, the efficacy and tolerability of two oral cannabinoid solutions were investigated alongside a placebo. These solutions encompassed a whole-plant cannabis extract (BOL-DP-O-01-W) with a 20:1 CBD-to-THC ratio and a purified version (BOL-DP-O-01) with the same ratio. Over 12 weeks, participants received cannabinoids or a placebo, followed by a 4-week washout and a 12-week cross-over phase. While primary outcome measures did not significantly differ among groups, improvements in disruptive behavior were notable—49% with the extract versus 21% with placebo. Adverse events like somnolence and decreased appetite were reported across groups, with no serious treatment-related issues. Despite limitations, the study underscores the tolerability of these solutions over 3 months and emphasizes the need for further cannabinoid research in ASD treatment.

CBD-rich Cannabis for ASD: An Open-Label Study

Expanding on the potential benefits of CBD-rich cannabis for children with ASD, a study published in Translational Psychiatry in 2022 investigated the effects of 6 months of treatment. Previous research relied on parental reports, lacking standardized assessments. Using standardized tools, this open-label study measured longitudinal changes in social communication abilities and restricted behaviors. Out of 110 participants, 82 completed the treatment protocol. While not all participants exhibited improvement, significant enhancements in social communication abilities were observed through standardized assessments. This improvement was more pronounced in participants with more severe initial symptoms.

Individually Tailored Cannabis Extracts: Advancing ASD Treatment

In a recent study, 20 patients with ASD symptoms underwent individualized treatment using full-spectrum cannabis extracts (FCEs). Dosages of cannabidiol (CBD) and tetrahydrocannabinol (THC) were meticulously adjusted based on responses from periodic clinical evaluations. Notably, 80% of patients received treatment for a minimum of six months. The study encompassed a comprehensive online survey covering core and comorbid symptoms and a thorough review of clinical records within the autism spectrum. This real-world approach sheds light on the extensive benefits FCEs offer for patients and families. The treatment started with CBD-rich FCEs for 18 patients, with three incorporating low doses of THC-rich FCEs for enhanced effects. Two patients utilized a blend of CBD-rich and THC-rich FCEs throughout. Positive outcomes were observed for most symptoms, with minimal side effects, confirming the safety and tolerability of this approach. Additionally, FCEs showcased the potential to treat allotriophagy (Pica) for the first time, leading to reduced use of other medications in most cases. The study suggests guidelines for individually tailored dosage regimens, paving the way for further trials using locally available qualified FCEs. This approach presents a new avenue for personalized interventions.

Conclusion

The journey to harness the potential of cannabinoid therapy for ASD is marked by exciting discoveries and the promise of effective, well-tolerated treatments. The ECS’s intricate involvement in the neurobiology of autism, coupled with CBD’s ability to modulate this system, opens new avenues for addressing the core symptoms and associated challenges faced by individuals with ASD. While significant strides have been made, including study results that highlight the superiority of full-spectrum extracts in managing symptoms, which is commonly seen in daily clinical practice, the road ahead demands rigorous research, encompassing clinical trials and biomarker investigations, to realize the full potential of cannabinoid therapy in enhancing the lives of those living with ASD.

References

• Aran, A., Harel, M., Cassuto, H., Polyansky, L., Schnapp, A., Wattad, N., Shmueli, D., Golan, D., & Castellanos, F. X. (2021). Cannabinoid treatment for autism: a proof-of-concept randomized trial. Molecular Autism, 12(1), 6. https://doi.org/10.1186/s13229-021-00420-2
• Carreira, L. D., Matias, F. C., & Campos, M. G. (2022). Clinical Data on Cannabinoids: Translational Research in the Treatment of Autism Spectrum Disorders. Biomedicines, 10(4), 796. https://doi.org/10.3390/biomedicines10040796
• Ferreira, L. F., Pathapati, N., Schultz, S. T., Nunn, M. C., Pierce, B. L., Sanchez, Y. R., Murrell, M. D., Ginsburg, B. C., Onaivi, E. S., & Gould, G. G. (2023). Acute cannabidiol treatment enhances social interaction in adult male mice. Advances in Drug and Alcohol Research, 3, 11163. https://doi.org/10.3389/adar.2023.11163
• Hacohen, M., Stolar, O. E., Berkovitch, M., Elkana, O., Kohn, E., Hazan, A., Heyman, E., Sobol, Y., Waissengreen, D., Gal, E., & Dinstein, I. (2022). Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study. Translational Psychiatry, 12(1), 375. https://doi.org/10.1038/s41398-022-02104-8
• Kwan Cheung, K. A., Mitchell, M. D., & Heussler, H. S. (2021). Cannabidiol and Neurodevelopmental Disorders in Children. Frontiers in Psychiatry, 12, 643442. https://doi.org/10.3389/fpsyt.2021.643442
• Pamplona, F. A., da Silva, L. R., & Coan, A. C. (2018). Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Frontiers in Neurology, 9. https://doi.org/10.3389/fneur.2018.00759
• Russo, E. B. (2018). Cannabis Therapeutics and the Future of Neurology. Frontiers in Integrative Neuroscience, 12. https://doi.org/10.3389/fnint.2018.00051
• Schiavi, S., Manduca, A., Carbone, E., Buzzelli, V., Rava, A., Feo, A., Ascone, F., Morena, M., Campolongo, P., Hill, M. N., & Trezza, V. (2023). Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats. Neuropsychopharmacology, 48(5), 897-907. https://doi.org/10.1038/s41386-022-01279-7
• Siani-Rose, M., Cox, S., Goldstein, B., Abrams, D., Taylor, M., & Kurek, I. (2023). 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, 8(1), 126-137. https://doi.org/10.1089/can.2021.0129
• Siani-Rose, M., McKee, R., Cox, S., Goldstein, B., Abrams, D., Taylor, M., & Kurek, I. (2023). The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder. Cannabis and Cannabinoid Research, 8(4), 642-656. https://doi.org/10.1089/can.2021.0224