Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity
Matthew B. Wall, Rebecca Pope, Tom P. Freeman, Oliwia S. Kowalczyk, Lysia Demetriou, Claire Mokrysz, Chandni Hindocha, Will Lawn, Michael A.P. Bloomfield, Abigail M. Freeman, Amanda Feilding, David J. Nutt and H. Valerie Curran
Journal of Psychopharmacology, 2019, 1–9
Background : Two major constituents of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC.
Aims : We examined the effects of two strains of cannabis and placebo on the human brain’s resting-state networks using fMRI.
Methods : Seventeen healthy volunteers (experienced with cannabis, but not regular users) underwent three drug treatments and scanning sessions. Treatments were cannabis containing THC (Cann−CBD; 8 mg THC), cannabis containing THC with CBD (Cann+CBD; 8 mg THC + 10 mg CBD), and matched placebo cannabis. Seed-based resting-state functional connectivity analyses were performed on three brain networks: the default mode (DMN; defined by positive connectivity with the posterior cingulate cortex: PCC+), executive control (ECN; defined by negative connectivity with the posterior cingulate cortex: PCC−) and salience (SAL; defined by positive connectivity with the anterior insula: AI+) network.
Results : Reductions in functional connectivity (relative to placebo) were seen in the DMN (PCC+) and SAL (AI+) networks for both strains of cannabis, with spatially dissociable effects. Across the entire salience network (AI+), Cann−CBD reduced connectivity relative to Cann+CBD. The PCC in the DMN was specifically disrupted by Cann−CBD, and this effect correlated with subjective drug effects, including feeling ‘stoned’ and ‘high’.
Conclusions : THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.
Keywords : Cannabis, cannabidiol, THC, fMRI, resting state, marijuana, default mode network, salience network
Cannabis has been used by humans for thousands of years for medical, spiritual and recreational purposes. Two of the main psychoactive ingredients of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). As well as making people ‘stoned’, THC produces amnestic, anxiogenic and psychotomimetic effects (including perceptual distortions, paranoia, disruptions of cognitive functions and euphoria; D’Souza et al., 2004) by acting as an agonist at endocannabinoid 1 (CB1) receptors (Pertwee, 2008). CBD’s effects have been less well studied, but early findings suggest it may have somewhat opposite effects, being anti-psychotic (Leweke et al., 2012) and perhaps anxiolytic (Bergamaschi et al., 2011). CBD is non-intoxicating and has a more complex neuropharmacological profile, including reducing the cellular reuptake and hydrolysis of anandamide, antagonism of the orphan receptor GPR55 and the 5-HT1A receptor, and antagonism of the CB1 receptor with a low affinity (Pertwee, 2008). THC is also largely responsible for providing many of the subjective effects of intoxication that recreational users seek (Curran et al., 2002). Concern has recently been raised about the high levels of THC found in modern cannabis, alongside minimal, if any, levels of CBD (ElSohly et al., 2016; Niesink et al., 2015). This high-strength cannabis (often referred to as ‘skunk’) is popular with users but is also hypothesized to be responsible for the dramatic increase in reporting of cannabis- related health issues in recent years, most notably addiction and cannabis-induced psychosis (Di Forti et al. 2009; Freeman et al., 2018; Freeman and Winstock, 2015). Because of its putatively opposing psychological and pharmacological effects, cannabis that contains higher levels of CBD may be a safer option on the basis that CBD may buffer the user against the main negative effects of THC (Curran et al., 2016; Englund et al., 2013; Hindocha et al., 2015; Niesink and van Laar, 2013). As cannabis transitions to legal/decriminalized status in many jurisdictions, understanding the neural effects of different strains of cannabis (with different levels of THC and CBD) is now a priority for public health. Functional magnetic resonance imaging (fMRI) is a popular method for indexing drug effects (Bourke and Wall, 2015; Iannetti and Wise, 2007), with restingstate fMRI (Fox and Raichle, 2007; De Luca et al., 2006) particularly useful, as it can derive results from multiple brain systems and provides a sensitive index of drug effects (e.g. Carhart-Harris et al., 2015; Kaelen et al., 2016). The default mode network (DMN) is perhaps the most prominent and wellstudied resting-state network, and its activity increases in periods of wakeful rest and during internally focused states such as autobiographical memory retrieval (Buckner et al., 2008). In contrast, its complementary network (the executive control network (ECN)) is most active when subjects are engaged in an external task (Fox et al., 2005). The salience network (Seeley et al., 2007) is involved in the detection of emotional and sensory stimuli and may be responsible for the switch between internally focused states supported by the DMN and externally focused states supported by the ECN (Goulden et al., 2014). Unfortunately, the differential effects of herbal cannabis with different concentrations of THC and CBD on these networks is largely unknown. Most previous neuroimaging studies using an acute drug challenge have focused on the effects of synthetic THC (e.g. Klumpers et al., 2012). Bossong and colleagues (2013) demonstrated acute disruptive effects of synthetic THC on the DMN, but in the context of an executive function task, with less effect on task-related brain regions. A recent study has also found similar results (reduction in default mode function) using the CB1-neutral antagonist tetrahydrocannibivarin (THCv; Rzepa et al., 2016). Another set of studies has compared oral synthetic THC and CBD and found opposite effects of the two treatments on a range of functional and perceptual tasks, including differing effects on brain regions involved in salience processing (Bhattacharyya et al., 2010, 2012, 2014; Winton-Brown et al., 2011). Further studies have focused on other resting-state connectivity networks, including corticostriatal connectivity (Grimm et al., 2018; Ramaekers et al., 2016) and the insula and frontal lobe (van Hell et al., 2011). Our aim was to use fMRI to directly investigate the effects of different strains of herbal cannabis on resting-state functional connectivity, using one strain containing high levels of THC but negligible levels of CBD (Cann−CBD) and another strain containing more balanced levels of THC and CBD (Cann+CBD). Both treatments were matched for total THC content and were compared with placebo cannabis (containing neither compound), which was well matched for terpene content and therefore had the same smell and appearance as active treatments. We hypothesized that the Cann−CBD treatment would induce more disruption (i.e. reductions in functional connectivity measures) in resting-state networks than the Cann+CBD strain.