Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy

Abstract

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies – including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites – markers of the brain’s primary excitatory and inhibitory system - in both the ‘typical’ and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the ‘shift’ in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

“…[80][81][82] Interestingly, in both the valproate model and Mecp2 mutant mice, CBDV reversed the alterations of eCBS proteins observed in the brain (such as the increased levels of CB 1 receptors). 80,82 In adults with ASD submitted to an MRS study, 83 CBDV (600 mg, single oral dose) produced, in the left basal ganglia, effects on glutamate-GABA signaling similar to those exerted by the same dose of CBD in the prefrontal cortex. 78…”

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

“…Participants were mainly children, even if in two studies there were mixed samples [53,54]. The three studies conducted by Pretzsch and colleagues [55][56][57] included only adults with normal cognitive abilities (IQ>70). Interestingly, only another study [58] has specified the level of functioning, which was not reported in the remaining papers.…”

“…McVige et al [60] documented the use of medical cannabis with unspecified composition. Finally, Pretzsch and colleagues administered single doses of 600 mg of CBD or CBDV [55][56][57]. Only the studies by Pretzsch et al used a control treatment (placebo).…”

“…Only the studies by Pretzsch et al used a control treatment (placebo). The duration of treatment was extremely variable, ranging from single administrations [55][56][57] to six months [51,52]. Of note, many studies were naturalistic and treatment duration was different among participants.…”

“…The three papers published by Pretzsch et al [55][56][57] have primarily investigated the modulation of brain's primary excitatory and inhibitory systems in adults with ASD and neurotypical controls after a single of 600 mg of cannabinoids (CBD and CBDV). The findings evidenced a CBD-related increase of glutamate (excitatory system) in subcortical regions (i.e.…”