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.
Highlights
Autism spectrum disorder (ASD) affects up to 1 in 59 individuals [1]
To be sure that our findings were not influenced by IQ, we investigated the relationship between drug-induced shifts (CBD-PLC) in metabolite levels (Glx and glutamate and inhibitory γ-aminobutyric acid (GABA)+) and IQ
Our results suggest that the structural and functional differences previously reported in magnetic resonance imaging (MRI) studies of corticalsubcortical systems in ASD extend to atypical E-I response to pharmacological challenge
Summary
Autism spectrum disorder (ASD) affects up to 1 in 59 individuals [1]. Of those affected, 70% have co-occurring conditions such as epilepsy [2], and mood and anxiety disorders [3]. Alongside anecdotal accounts and case series reports of benefits from medical marijuana in ASD [10], there is evidence that CBD: (i) reduces seizure frequency in two epilepsy syndromes associated with autistic symptoms: Dravet Syndrome and Lennox–Gastaut syndrome [11,12,13]; and (ii) improves ASD-like social deficits in a mouse model of Dravet Syndrome [14]. This suggests that CBD may be worth further investigation in idiopathic ASD. Before embarking on large-scale clinical trials, a better understanding of how CBD acts on the human brain, and especially in ASD, would be desirable
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