Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder

Abstract

There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD ‘shifts’ glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

The Transcriptomic Analysis of NSC-34 Motor Neuron-Like Cells Reveals That Cannabigerol Influences Synaptic Pathways: A Comparative Study with Cannabidiol

“…The CBG quinone derivative VCE-003.2 was reported to be able to reduce glial glutamate transporters [ 24 ]. On the contrary, CBD is known to be involved in the regulation of the excitatory transmission of glutamate and the inhibitory transmission of GABA [ 25 ]. In particular, CBD appears to be a GABA A receptor modulator, being able to increase GABA-evoked currents [ 26 ].…”

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

“…76 Two brain imaging studies, one with functional magnetic resonance imaging (fMRI) and the other with magnetic resonance spectroscopy (MRS), have shown that CBD (600 mg, single oral administration) modulates the glutamate-GABA systems and the low-frequency activity and functional connectivity in the brains of adults with ASD in a manner different from their controls. 77,78 Since studies with CBD in animal models of ASD are still lacking, it is difficult to assess through what mechanism of action this phytocannabinoid exerts these effects, as well as to what extent they are related to clinical efficacy, which, however, still needs to be confirmed in double-blind placebo-controlled trials (see Poleg et al 79 for a recent review).…”

“…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.…”