The current review provides a systematic literature overview of studies that investigated the acute effects of CBD on the human brain of healthy volunteers and individuals diagnosed with a psychiatric disorder. Overall, studies in healthy subjects showed that CBD modulated brain activity and had opposite effects when compared to THC in resting state and during several cognitive paradigms (i.e., salience, emotional, memory, response inhibition, auditory/visual processing), following task-specific activation patterns. Acute CBD administration also modulated brain activity in patients with psychiatric disorders by 1) showing intermediate activity compared to placebo and healthy controls in individuals at CHR and with established psychosis, 2) engaging with resting limbic activity in subjects with anxiety disorders, and 3) exhibiting similar (glutamate) and opposite (GABA) metabolite levels in patients with autism compared to healthy controls.

The acute administration of CBD in healthy volunteers modulated networks relevant for psychiatric disorders during resting state and several cognitive tasks, such as fronto-striatal and fronto-limbic circuitry. Fronto-striatal connectivity was enhanced after CBD administration during resting state (Grimm et al., 2018) and activity increased during salience processing (Bhattacharyya et al., 2015). Interestingly, lower functional connectivity in fronto-striatal circuitry has been reported in psychosis, and has been associated with more severe positive symptoms (Fornito et al., 2013). In addition, CBD decreased fronto-limbic activity during resting state (Crippa et al., 2004) and emotional processing (Fusar-Poli et al., 2010). Functional fMRI studies have shown activation of limbic areas in anxiety disorders (e.g., during panic attacks or panic anticipation) (Pfleiderer et al., 2007; Dresler et al., 2013). Based on a mechanistic account of these networks, these findings suggest that CBD might prove useful as treatment by restoring imbalanced networks in these and probably other neurological (Nenert et al., 2020) and psychiatric conditions, such as substance use disorders (Freeman et al., 2020). Regarding the last, converging preclinical and clinical evidence have shown promising effects of CBD on reducing craving, negative affect and motivation for substance use (Chye et al., 2019; Hurd et al., 2019; Freeman et al., 2020; Spanagel, 2020), phenomena associated with fronto-striatal and limbic network disbalances (Koob and Volkow, 2016; Volkow and Boyle, 2018).

Along these lines, CBD also showed opposite effects compared to THC during resting state and several cognitive paradigms in healthy volunteers. It is known that THC has pro-psychotic and anxiogenic properties, particularly evident with high potency cannabis strains (rich in THC) and at high doses (Campeny et al., 2020; Van der Steur et al., 2020). Opposite neurophysiological effects were reported on prefrontal, striatal and limbic areas, which are relevant neural substrates of psychosis and anxiety, and during several cognitive processes, such as salience, verbal memory, response inhibition, emotional processing and auditory/visual processing. Importantly, striatum activity correlated with severity of psychotic symptoms after THC (Bhattacharyya et al., 2010; Bhattacharyya et al., 2012b), and divergent amygdala activity correlated with severity of anxiety after CBD and THC (Bhattacharyya et al., 2010). These opposite brain effects may therefore underlie the neural basis for the antipsychotic and anxiolytic properties of CBD, and suggest that CBD might be able to counterbalance THC induced effects (Colizzi and Bhattacharyya, 2017). However, CBD concentrations needed to offset the effects of THC in healthy individuals are still unclear, as CBD might also have different effects when administered at different doses (Solowij et al., 2019).

Acute CBD administration also affected brain networks of subjects diagnosed with a psychiatric disorder. In individuals at CHR for psychosis, CBD showed intermediate activity compared to patients receiving placebo and healthy subjects in regions involved in reward and salience processing (Bhattacharyya et al., 2018; Wilson et al., 2019). A similar intermediate activity was reported in subjects with established psychosis during a memory task (O’Neill et al., 2020). These findings are consistent with the enhanced activity observed in fronto-striatal regions in healthy subjects after CBD (Bhattacharyya et al., 2015; Grimm et al., 2018). Altogether, these findings suggest that CBD could contribute to normalise disbalanced fronto-striatal activity in patients at CHR or with established psychosis. In addition, Crippa and colleagues showed that CBD reduced cerebral blood flow in (para) limbic areas (i.e., hippocampus, parahippocampal and inferior temporal gyrus) in subjects with social anxiety (Crippa et al., 2011). This is congruent with decreased fronto-limbic activity in healthy individuals reported after CBD (Crippa et al., 2004; Fusar-Poli et al., 2010), and suggest that the anxiolytic effects of CBD may be related to the capacity of this compound to modify brain activity in (para) limbic areas (Crippa et al., 2011). Finally, a spectroscopy study in autism spectrum disorder and healthy controls showed similar glutamate (i.e., increased in basal ganglia, and decreased in prefrontal cortex in both groups) and opposite GABA (i.e., decreased levels in patients and increased in controls in both basal ganglia and prefrontal cortex) effects after CBD administration (Pretzsch et al., 2019). This study adds to preclinical evidence that CBD may modulate the activity of other neurotransmitters, even after a single dose (Crippa et al., 2018). This has implications for the homeostasis of other neurotransmitter systems, such as glutamate, GABA and dopamine. However, the underlying molecular mechanisms explaining the relationship between CBD and other neurotransmitters needs further study.

One of these molecular mechanisms may involve the ability of CBD to directly inhibit the reuptake of anandamide. This endocannabinoid has shown anti-inflammatory activity (Pisanti et al., 2017), and its increase after CBD has been related to antipsychotic effects (Leweke et al., 2012; Rohleder et al., 2016). Because endocannabinoids act as retrograde messengers, it has been hypothesized that increased endocannabinoid concentrations after CBD may attenuate presynaptic release of GABA and glutamate, as well as stabilise dopamine neurotransmission (Gururajan and Malone, 2016). In addition, most of the reported effects after CBD administration occurred in brain areas rich in CB₁ receptors (Burns et al., 2007). Chronic cannabis use is associated with reductions in endogenous cannabinoids and down-regulation of CB₁ receptors (Hirvonen et al., 2012; Morgan et al., 2013), while CBD antagonistic effects could be related to modulation of cannabinoid receptors by binding to a distinct allosteric site (Laprairie et al., 2015). Given that CBD may attenuate THC effects, it has also been speculated that CBD may be able to prevent down-regulation of CB₁ receptors on the long-term, and thus decrease the risk of developing psychosis and/or substance use disorders (Wall et al., 2019). Other possible mechanisms of action of CBD involve its agonist activity towards 5HT_1A receptors (Soares and Campos, 2017), partial agonist activity on dopamine D2 receptors (Seeman, 2016), and the activation of vanilloid receptor 1, a non-selective calcium channel, facilitating glutamate pre-synaptic release (Campos et al., 2012).

This review must be read with a series of limitations taken into account. First, included papers often employed different methodologies (e.g., imaging method, route of administration, applied doses), although we used strict inclusion and exclusion criteria for article selection to avoid excessive heterogeneity between studies. For example, whereas most studies administered CBD and THC as individual cannabinoid compounds in separate sessions (Borgwardt et al., 2008; Bhattacharyya et al., 2012b; Grimm et al., 2018), some studies examined the impact of CBD on brain function by comparing effects of cannabis containing THC only to cannabis with both THC and CBD (Freeman et al., 2018; Wall et al., 2019). Regarding differences in applied cognitive paradigms, it is important to note that the described effects on brain activity might depend on the nature of the task used or stimuli presented, as different tasks might provoke distinct brain activity patterns. For instance, whereas memory paradigms may heavily rely on recruitment of temporal and prefrontal areas (Bhattacharyya et al., 2009; Bhattacharyya et al., 2018; O’Neill et al., 2020), emotional and salience processing mainly involve limbic activation (Fusar-Poli et al., 2009; Bhattacharyya et al., 2012b). One final methodological aspect that should be taken into account is that the clinical and brain effects of CBD might be different depending on age and illness progression (Di Marzo et al., 2015; Batalla et al., 2019; Colizzi et al., 2020), or be influenced by the concomitant use of medication (e.g., antipsychotics) or drugs of abuse. However, the within-subject design of the studies where concomitant use of medication or cannabis was allowed probably mitigated these confounding effects (Table 3). Second, most of the included studies used overlapping samples of mainly male healthy subjects or patients with psychiatric disorders to explore the effects of CBD. Although the studies reviewed herein offer a consistent picture indicating that CBD has modulatory effects over neural networks relevant for psychosis, anxiety and addiction, this highlights the need for replication of findings in independent and larger cohorts also including female subjects.

Suggestions can be made for future research on the impact of CBD on brain function. First, because all studies included in the current review examined the acute effects of CBD administration, future research should focus on longer-term CBD treatment of patients with a psychiatric disorder in combination with neuroimaging assessments, in order to elucidate neural substrates underlying the therapeutic effects of CBD. In this respect, two excellent examples of studies nearing completion are 1) 3 weeks CBD treatment of individuals at CHR for psychosis (Institute of Psychiatry, King’s College London), and 2) 4-week add-on CBD treatment of early-onset patients with a psychotic disorder (University Medical Center Utrecht, Netherlands), both in combination with baseline and follow-up functional MRI and ¹H-MRS techniques. Second, because the clinical response to CBD has been shown to differ between patients (Batalla et al., 2019), future studies could also apply neuroimaging techniques to contribute to identification of those patients that may particularly benefit from CBD treatment.

In conclusion, neuroimaging studies have shown that CBD modulates brain activity and connectivity in neural systems relevant for psychosis and anxiety, possibly reflecting CBD’s therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longer-term CBD treatment with neuroimaging assessments.