The Non-Psychoactive Cannabinoid Cannabidivarin (CBDV) Modulates the Functional Connectivity of the Default Mode Network in Adults with ASD but Not in Controls.

Background: Research in epilepsy indicates that the brain’s endocannabinoid system is an important regulator of neural activity. The endocannabinoid system has also been suggested as a treatment target in conditions linked to epilepsy, including autism spectrum disorder (ASD). However, there is no direct evidence that cannabinoids regulate brain function differently in ASD compared to controls.

Objectives: Therefore, the aim of this pilot study was to compare brain network activity in otherwise healthy men with and without ASD following a single dose of cannabidivarin (CBDV), using functional MRI. We focused on the dorsal and ventral Default Mode Network (DMN) because of the DMN's role in social and self-reflective processes, known to be affected in ASD.

Methods: A total of 19 adults with ASD and 19 healthy controls (age-matched) were recruited to a double-blind, randomised, cross-over design. Scans were acquired 2 hours (corresponding with peak plasma levels) after oral administration of either placebo or CBDV; and were a minimum of 13 days apart to ensure adequate drug wash-out between scans. We conducted pre-planned contrasts tested with non-parametric inference at a false discovery rate (q=0.05) to examine significant DMN functional connectivity (FC): i) group differences (control n = 19; ASD n = 19) at baseline (placebo); and ii) group differences (control n = 15; ASD n = 13) in the CBDV condition.

Results: There was no statistically significant between-group difference in the dorsal or ventral DMN at baseline; there was no group difference in the dorsal DMN in the CDBV condition. However, there was a significant group difference in FC of the ventral DMN in the CBDV condition. Specifically, the ASD group had lower FC than controls between the left parahippocampal gyrus and the right posterior cingulate cortex (t(26) = 4.78, p<.0001, d = 1.80) and between the right parahippocampal gyrus and left posterior cingulate cortex (t(26) = 3.44, p=.04, d = 1.32). Post hoc testing within groups revealed that CBDV caused a significant reduction in FC between the left parahippocampal gyrus and the right posterior cingulate cortex compared to baseline (t(28) = -2.5, p=.02, d = 0.91) in ASD only; and no change in controls.

Conclusions: Our results reveal a difference in responsivity to CDBV in individuals with and without ASD. Whether this translates into a therapeutic response, and/or provides a means to identify individuals with ASD who may respond to CBDV, is not known; but this deserves further study.