Cannabidiol (CBD) Alters Low Frequency Activity and Functional Connectivity in the Brain in Autism Spectrum Disorder (ASD).

Background: The potential benefits of cannabis and its major non-intoxicating component cannabidiol (CBD) are attracting increasing attention for treating mental health conditions and neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the mechanisms of action of CBD in the brain, and their relevance to ASD, remain unclear. We and others have previously shown that responsivity to pharmacological challenge, such as brain function, can be measured using functional magnetic resonance imaging (fMRI); but that there are differences in pharmacological responsivity in individuals with and without ASD.

Objectives: Therefore, we used fMRI to examine brain responsivity to CBD in adults with and without ASD.

Methods: Thirty-four healthy men (half with ASD) participated in a placebo-controlled, double blind cross-over study of responsivity to an acute oral administration of 600 mg CBD and placebo. We first conducted a hypothesis-free whole-brain analysis of the ‘fractional Amplitude of Low Frequency Fluctuations’ (fALFF) in brain activity. Significance was set at p < 0.05 (using Threshold Free Cluster Enhancement (TFCE)) with family-wise error correction. Next, in regions where CBD significantly changed fALFF, we examined whether this was accompanied by any shift in the functional connectivity (FC) between those regions and the rest of the brain (using seed-based analysis). Data acquisition was timed to commence (at peak plasma levels) 2 hours after administration of CBD or placebo.

Results: CBD significantly increased fALFF in the cerebellar vermis and the right fusiform gyrus from a comparable baseline across both groups. However, post-hoc within-group analyses revealed that the effect of CBD was primarily driven by the ASD group, with no significant change in controls. Within the ASD group only, CBD also significantly altered FC between the vermis and several of its subcortical (striatal) and cortical targets. The FC of the fusiform was not significantly altered by CBD in either group.

Conclusions: In autistic adults, CBD boosts regional fALFF in the vermis and fusiform – brain areas that have consistently been linked to social and cognitive processing differences in ASD. In addition, CBD shifted cerebellar, but not fusiform, FC in ASD. This may be because the cerebellum has a rich network of connections, compared with the relatively more restricted connections of the fusiform. However, the autistic brain appears to be more pharmacologically responsive to an acute dose of CBD than the typical brain, especially in regions consistently implicated in the condition. Future studies are required to determine if the CBD-induced alterations of brain activity and connectivity in ASD also affect the complex behaviours these regions modulate.