The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD), Charlotte M Pretzsch et al., 2019

The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD)

Charlotte M. Pretzsch, Bogdan Voinescu, Maria A. Mendez, Robert Wichers, Laura Ajram, Glynis Ivin, Martin Heasman, Steven Williams, Declan GM Murphy, Eileen Daly and Gráinne M. McAlonan

Journal of Psychopharmacology, 2019, Vol. 33, (9), 1141–1148

Doi : 10.1177/0269881119858306



Background : The potential benefits of cannabis and its major non-intoxicating component cannabidiol (CBD) are attracting attention, including as a potential treatment in neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the neural action of CBD, and its relevance to ASD, remains unclear. We and others have previously shown that response to drug challenge can be measured using functional magnetic resonance imaging (fMRI), but that pharmacological responsivity is atypical in ASD.

Aims : We hypothesized that there would be a (different) fMRI response to CBD in ASD.

Methods : To test this, task-free fMRI was acquired in 34 healthy men (half with ASD) following oral administration of 600 mg CBD or matched placebo (random order; double-blind administration). The ‘fractional amplitude of low-frequency fluctuations’ (fALFF) was measured across the whole brain, and, where CBD significantly altered fALFF, we tested if functional connectivity (FC) of those regions was also affected by CBD.

Results : CBD significantly increased fALFF in the cerebellar vermis and the right fusiform gyrus. However, post-hoc within group analyses revealed that this effect was primarily driven by the ASD group, with no significant change in controls. Within the ASD group only, CBD also significantly altered vermal FC with several of its subcortical (striatal) and cortical targets, but did not affect fusiform FC with other regions in either group.

Conclusion : Our results suggest that, especially in ASD, CBD alters regional fALFF and FC in/between regions consistently implicated in ASD. Future studies should examine if this affects the complex behaviours these regions modulate.

Keyword : Cannabidiol, autism spectrum disorder, low-frequency fluctuations, functional connectivity, Cannabis sativa



Autism spectrum disorder (ASD) is a common (Baio et al., 2018) and complex neurodevelopmental psychiatric condition, which shortens life expectancy by up to 20 years (Hirvikoski et al., 2016). Moreover, 70% of autistic individuals are estimated to have co-occurring conditions, e.g. epilepsy (Tuchman and Rapin, 2002) and mood and anxiety disorders (Joshi et al., 2013).

However, there are no effective pharmacological treatments for the core symptoms of ASD, and individuals often respond poorly to conventional treatments of complicating mental or physical illnesses. Alternative treatment approaches, such as cannabis and its major non-intoxicating component cannabidiol (CBD) (Fetterman and Turner, 1972), are therefore increasingly explored.

There is accumulating evidence for the efficacy of CBD in several conditions, such as spasticity in multiple sclerosis (Zajicek et al., 2003) and schizophrenia (Bhattacharyya et al., 2018); and in conditions associated with ASD, including social phobia (Bergamaschi et al., 2011) and epilepsy (Devinsky et al., 2016). Moreover, there are preliminary reports of beneficial effects of medical marihuana in idiopathic ASD itself (Aran et al., 2018; Campbell et al., 2017). For instance, a recent study has demonstrated that CBD-rich cannabis reduced behavioural outbreaks in children with ASD and severe behavioural problems (Aran et al., 2018). Thus, a role for CBD in ASD management warrants further attention. Consequently, there are now at least two clinical trials of CBD in ASD (; identifiers NCT03900923 and NCT02956226). However, we still
have only limited understanding of how the typical human brain, let alone the autistic brain, responds to CBD. Hence, a fuller understanding of the mechanism of action of CBD on the brain, and its relevance to ASD, is desirable before investing in largescale clinical trials.

Brain responsivity to pharmacological challenges can, for example, be measured using functional magnetic resonance imaging (fMRI) (Bhattacharyya et al., 2015; Fusar-Poli et al., 2010; Grimm et al., 2018). Evidence that such approaches are sensitive to CBD effects comes from studies in both neurotypicals and individuals with schizophrenia. For instance, in neurotypicals, CBD reduced fronto striatal – and decreased mediotemporal-prefrontal – FC during a visual oddball salience task, and enhanced salience processing (Bhattacharyya et al., 2015). In neurotypicals, CBD also disrupted prefrontal-subcortical connectivity during the processing of fearful faces (Fusar-Poli et al., 2010), and increased fronto-striatal activity at rest (Grimm et al., 2018). In schizophrenia, an acute dose of CBD was reported to ‘normalize’ brain activity in regions during a verbal learning paradigm (Bhattacharyya et al., 2018). Similarly, fMRI has been used as a marker for other drug challenges in ASD, such as riluzole, propranolol or oxytocin (Ajram et al., 2017; Gordon et al., 2016; Narayanan et al., 2010). However, the vast majority of these previous studies acquired fMRI during cognitive tasks.