Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication, and restricted and repetitive patterns of behavior, interests, or activities. These are often accompanied by intellectual disabilities. At present, there is no designated effective treatment for the core symptoms and co-morbidities of ASD. Recently, interest is rising in medical cannabis as a treatment for ASD, with promising clinical data. However, there is a notable absence of basic pre-clinical research in this field. In this study, we investigate the behavioral and biochemical effects of long-term oral treatment with CBD-enriched medical cannabis oil in a human mutation-based Shank3 mouse model of ASD. Our findings show that this treatment alleviates anxiety and decreases repetitive grooming behavior by over 70% in treated mutant mice compared to non-treated mutant mice. Furthermore, we were able to uncover the involvement of CB1 receptor (CB1R) signaling in the Avidekel oil mechanism, alongside a mitigation of cerebrospinal fluid (CSF) glutamate concentrations. Subsequently, RNA sequencing (RNA seq) of cerebellar brain samples revealed changes in mRNA expression of several neurotransmission-related genes post-treatment. Finally, our results question the relevancy of CBD enrichment of medical cannabis for treating the core symptoms of ASD, and emphasize the importance of the THC component for alleviating deficits in repetitive and social behaviors in ASD.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation
Concentrations of cannabinoids in the serum of InsG3680 Shank3 mutant mice In a series of liquid chromatography-mass spectrometry (LC-MS) tests, concentrations of exocannabinoids as well as endocannabinoids in the serum of InsG3680 Shank3 mutant mice were measured, so as to evaluate the effect of Avidekel oil treatment on RESULTS CBD-enriched medical cannabis treatment improves repetitive and anxiety behaviors, but not social deficits, in InsG3680 Shank3 mouse model of ASD In conducting this experiment, our prime goal was to assess the effects of long-term treatment with CBD-enriched medical cannabis on the autistic-like phenotypes of InsG3680 Shank3 mouse model of ASD (Fig. 2B)
Treatment with Avidekel oil led to high concentrations of CBD and THC in the serum one hour posttreatment, and the CBD:THC ratio of 20:1 that was reported by the manufacturer was preserved (Fig. 3D, E)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication; restricted and repetitive patterns of behavior, interests, or activities. In InsG3680 Shank mutant mice, a point mutation that was identified in genetic screens of individuals with ASD causes a stop codon immediately after the G insertion in position 3680, thereby causing an almost complete loss of SHANK3 protein. This mouse model demonstrates prominent autistic-like behaviors, such as impaired social interaction, anxiety, and excessive repetitive selfgrooming that leads to skin lesions in ~30% of the adult homozygous mice [7] (Fig. 2A)
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