The Impact of Cannabidiol on Human Brain Function : A Systematic Review, Albert Batalla et al., 2021

The Impact of Cannabidiol on Human Brain Function : A Systematic Review

Albert Batalla, Julian Bos, Amber Postma and Matthijs G. Bossong

Frontiers in Pharmacology, January 2021 | Volume 11 | Article 618184, 1-15.

doi : 10.3389/fphar.2020.618184


Background : Accumulating evidence suggests that the non-intoxicating cannabinoid compound cannabidiol (CBD) may have antipsychotic and anxiolytic properties, and thus may be a promising new agent in the treatment of psychotic and anxiety disorders. However, the neurobiological substrates underlying the potential therapeutic effects of CBD are still unclear. The aim of this systematic review is to provide a detailed and up-todate systematic literature overview of neuroimaging studies that investigated the acute impact of CBD on human brain function.

Methods : Papers published until May 2020 were included from PubMed following a comprehensive search strategy and pre-determined set of criteria for article selection. We included studies that examined the effects of CBD on brain function of healthy volunteers and individuals diagnosed with a psychiatric disorder, comprising both the effects of CBD alone as well as in direct comparison to those induced by Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis.

Results : One-ninety four studies were identified, of which 17 met inclusion criteria. All studies investigated the acute effects of CBD on brain function during resting state or in the context of cognitive tasks. In healthy volunteers, acute CBD enhanced fronto-striatal resting state connectivity, both compared to placebo and THC. Furthermore, CBD modulated brain activity and had opposite effects when compared to THC following task-specific patterns during various cognitive paradigms, such as emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbicstriatal), and auditory/visual processing (temporo-occipital). In individuals at clinical high risk for psychosis and patients with established psychosis, acute CBD showed intermediate brain activity compared to placebo and healthy controls during cognitive task performance. CBD modulated resting limbic activity in subjects with anxiety and metabolite levels in patients with autism spectrum disorders.

Conclusion : Neuroimaging studies have shown that acute CBD induces significant alterations in brain activity and connectivity patterns during resting state and performance of cognitive tasks in both healthy volunteers and patients with a psychiatric disorder. This included modulation of functional networks relevant for psychiatric disorders, possibly reflecting CBD’s therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longerterm CBD treatment with neuroimaging assessments.

Keywords : cannabidiol, delta9-tetrahydrocannabinol, Cannabis (marijuana), neuroimaging, functional MRI



Recently, there has been a growing interest in cannabidiol (CBD) as a therapeutic substance, due to its putative antipsychotic, anxiolytic and anti-craving effects (Iseger and Bossong, 2015; Rohleder et al., 2016; Batalla et al., 2019). CBD is one of the more than 100 cannabinoids that can be derived from the cannabis plant and is, unlike the main psychoactive compound delta-9- tetrahydrocannabinol (THC), devoid of intoxicating effects (Freeman et al., 2019). Since most conventional treatments in psychiatry, such as antipsychotics and antidepressants, are associated with limited response rates and adverse events that often limit tolerability and adherence (Blessing et al., 2015; Samara et al., 2019), there is an urgent need for developing novel pharmaceutical treatments (Leucht et al., 2013; Blessing et al., 2015; Lally and MacCabe, 2015). In this regard, CBD has been proposed as novel therapeutic compound in several psychiatric disorders, such as psychosis (Iseger and Bossong, 2015; Batalla et al., 2019), anxiety disorders (Blessing et al., 2015), substance use disorders (Chye et al., 2019; Freeman et al., 2020) and autism spectrum disorders (Poleg et al., 2019; Fusar-Poli et al., 2020).

CBD effects are most likely related to the endocannabinoid system (Rohleder et al., 2016), although its precise mechanism of action is not yet fully understood. Animal studies have shown that CBD has no significant affinity with the cannabinoid receptors CB1 and CB2 (Bisogno et al., 2001; Jones et al., 2010), but may act as an antagonist of both in presence of CB1 agonists (Thomas et al., 2007). It has been hypothesized that the antagonistic effects of CBD might be through negative allosteric modulation of the CB1 receptor (Laprairie et al., 2015; Rohleder et al., 2016). Other suggested molecular targets include different types of receptors, such as serotonin type 1A (5HT1A), peroxisome proliferatoractivated receptor gamma (PPARgamma), vanilloid receptor 1 (TRPV1), GPR55, and GPR18 (Pertwee, 2008; Gururajan and Malone, 2016). In addition, CBD has been shown to increase plasma levels of the endogenous cannabinoid anandamide, which was related to its antipsychotic effects (Leweke et al., 2012). Hence, CBD may exert a protective effect on disturbances of the endocannabinoid system, as observed in several psychiatric disorders (Leweke et al., 2007; Morgan et al., 2013; Minichino et al., 2019).

Neuroimaging techniques provide a highly useful insight into the human neural processes involved in the behavioral effects of cannabinoids. An increasing number of neuroimaging studies have been performed to examine the human neural mechanisms underlying the effects of CBD. Although some of these studies have been included in excellent reviews that describe the impact of cannabis on human brain function in a broader context (Martín-Santos et al., 2010; Bhattacharyya et al., 2012a; Batalla et al., 2014; Weinstein et al., 2016), the aim of the current review is to provide a systematic and up-to-date overview of neuroimaging studies that investigated the effects of CBD on human brain function. This includes studies that examined the impact of CBD on brain function of healthy volunteers, comprising both the acute effects of CBD alone as well as in direct comparison to those induced by THC, and studies that investigated the neural substrates of acute CBD effects in patients with a psychiatric disorder.