In the following sections we will review evidence suggesting that neurophysiological, neurocognitive, genetic, and brain morphological abnormalities may contribute to the comorbidity of CUDs in schizophrenia.

Neurophysiology

Studies have documented neurophysiological impairments in both schizophrenia patients and otherwise healthy cannabis users. Transcranial magnetic stimulation (TMS) is a non-invasive technique that is used to index cortical inhibition and excitability. Moreover, GABA A and GABA B receptor-mediated inhibitory neurotransmission can be differentially indexed through single and paired TMS protocols. Among patients with schizophrenia, several studies have demonstrated pervasive cortical inhibition deficits. For example, Daskalakis et al. [41] reported pervasive GABA B deficits in the motor and DLPFC using TMS-EEG. In healthy cannabis users, Fitzgerald et al. examined light versus heavy cannabis use in healthy controls, and reported reduced cortical inhibition regardless of cannabis use status [42]. Wobrock et al. [43•] conducted a study in first-episode patients with schizophrenia who used cannabis, and reported deficits in cortical inhibition selective to GABA A receptor activity compared with non-using patients. Given that these studies are cross-sectional, it is not clear if cannabis produces such deficits. We posit that these deficits in GABA activity increase the likelihood of engaging in cannabis use. Moreover, indices of cortical inhibition have been strongly correlated with working memory performance in healthy subjects and may be important in modulating high-frequency oscillations in the DLPFC that influences working memory [44]. Given that schizophrenia is related to abnormal neural oscillations [45] and that cannabis has been associated with similar impairments, this supports our hypothesis that common underlying substrates may lead to the development of comorbid CUDs in schizophrenia.

Prepulse inhibition (PPI) of the startle response involves an attenuation of responsiveness to a sudden-onset high-intensity stimulus when the stimulus is immediately preceded by a lower-intensity stimulus. PPI is an operational measure of sensorimotor gating that may underlie cognitive symptoms of the schizophrenia [46, 47], but the additional effects of cannabis are less clear. Kedzior and Martin-Iverson [47] impaired attentional modulation and reduced PPI among chronic users relative to controls. Other studies are consistent with these results [48, 49], but not all [50]. In examining the interaction between schizophrenia and cannabis use on PPI, impaired modulation of PPI was demonstrated in schizophrenia patients (users and non-users) and in control users compared with non-cannabis-using controls [51]. PPI deficits are clinically important, given that they may be predictive of or lead to further disruption of cognition [52]. A study conducted by Kedzior et al. [53] suggests that neural oscillations may mediate these deficits, which is expected given that abnormal neural oscillations have been reported in both schizophrenia and CUDs [45, 54].

Amplitude changes in P50 event-related potentials during a dual-click conditioning–testing procedure has been proposed as a neurophysiological marker of deficient sensory gating in schizophrenia [55]. Sensory gating is the brain’s ability to modulate its sensitivity to irrelevant sensory stimuli and thus filter out repetitive and redundant sensory stimulation [46]. Cross-sectional studies report both disrupted and intact P50 in cannabis-using schizophrenia patients [56, 57]. Despite the lack of gating differences in these patient studies, it is interesting to note that P50 gating deficits in heavy chronic cannabis users have been linked to abnormal oscillatory activity [58, 59], which is similarly disrupted in schizophrenia patients [45].

Taken together, neurophysiology studies suggest that alterations in cortical inhibition, attention and sensory gating may be related to alterations in oscillations mediated by GABAergic inhibitory neurotransmission in both schizophrenia and CUDs. Thus, while further evidence is needed, preliminary data suggest similar underlying pathophysiology exists between schizophrenia and CUDs.

Neurocognition

Cognitive deficits are core features of schizophrenia, and most prominent impairments are observed in the domains of working and verbal memory and attention. While consistent impairments are seen in non-psychiatric individuals who engage in cannabis use [60], equivocal findings of associations exist between cannabis and schizophrenia. In 2005, D’Souza and colleagues elegantly demonstrated the detrimental effects cannabis has on cognitive performance [5]. Their group showed that cannabis dose-dependently impairs verbal memory and attention in both schizophrenia patients and controls, with the former group having enhanced sensitivity to these effects. While evidence suggests better cognition in cannabis-dependent patients compared with non-using patients [61], this does not imply improved cognition as a result of cannabis use. This observation likely reflects that patients who engage in cannabis use have a better premorbid IQ and better social cognition that those who do not [61, 62]. A recently published study by our group speaks to this effect. We showed that while there is a strong relationship between cannabis consumption and cognitive impairment in current cannabis users, such an association is absent in former users. This suggests that abstinence may reverse cannabis-induced impairments [63•], especially in domains of memory, mediated by the hippocampus, a structure rich in CB1R.

Taken together, similar cognitive deficits are observed in both patients with schizophrenia and with cannabis use in controls, particularly in the attention, working memory, and verbal memory domains.

Genetics

Genetic variants that influence dopamine represent interesting candidates that may contribute to this comorbidity given its role in schizophrenia [64] and addiction [65]. Catechol-O-methyltransferase (COMT) gene encodes the enzyme responsible for the degradation of dopamine and is essential for dopamine signalling in the prefrontal cortex ( PFC) [66]. COMT activity is genetically polymorphic, with high enzymatic activity in the Val/Val genotype, intermediate activity in the Val/Met genotype, and low activity in the Met/Met genotype; with increased enzymatic activity there is a greater overall reduction in synaptic dopamine availability. Caspi et al. [67] demonstrated that individuals homozygous for the Val158 allele were more likely to display psychotic symptoms and exhibit an earlier age of onset if they used cannabis in adolescence. Henquet et al. [68] showed that patients and their first-degree relatives homozygous for the Val allele showed an increased sensitivity to THC-induced psychotic symptoms and diminished attention and memory. However, this association has not been found in other studies [26] and thus the contribution of COMT to the cannabis–psychosis relationship remains under investigation.

The AKT1 gene codes for a protein kinase that forms an integral part of the dopamine receptor signaling cascade in the striatum [69]. This gene has been linked to schizophrenia [70], and in vitro studies have shown that cannabinoids are capable of stimulating the AKT1 pathway via CB1R [71]. Polymorphisms in this gene may increase the risk of schizophrenia in the presence of cannabis use [72, 73]. These investigators also reported an AKT1–cannabis interaction on cognitive performance in that patients with the C/C genotype performed significantly worse on a test of sustained attention compared with T/T carriers [74]. Preliminary experimental evidence has also implicated a different polymorphism of the AKT1 gene (the GG genotype of the SNP rs1130233) as a moderator of sensitivity to the acute psychosis-inducing effect of THC [75]. Further characterization of these variants in this comorbidity is warranted.

While single genetic variants represent attractive candidates for increasing vulnerability to comorbidity, current evidence is weak. Analysis of whole genome sequence data may uncover alternative genetic contributors; however, it is likely a number of genes, rather than a single polymorphism or variant of one gene, contribute to comorbidity in schizophrenia. Future genetic research warrants large samples that use prospective designs in order to reach more definitive conclusions regarding the genetic influence on this comorbidity.

Structural Brain Morphology Changes

Regional and global morphological abnormalities such as ventricular enlargements and decreased brain volume have been documented in the frontal and temporal lobes of patients with schizophrenia [76]. Moreover, morphological changes have been shown to pre-date the first episode of psychosis, suggesting that structural irregularities set the stage for the development of schizophrenia [77].

With respect to associations between cannabis and brain abnormalities, significant volume reductions of the (para-) hippocampus, amygdala, and cerebellum have been reported in adult heavy cannabis users compared with controls [78, 79]. However, a review of other studies reports contrary results, suggesting that cannabis use has no effect on gray- or white-matter volume [80].

Among schizophrenia patients, cannabis use reportedly has a detrimental effect on grey-matter density in various brain regions [81, 82]. In adolescent-onset schizophrenia, cannabis use was associated with grey-matter density loss in widespread cortical areas and the cerebellum [83]. A study that focused specifically on the cerebellum demonstrated an addictive effect of having a diagnosis of schizophrenia and cannabis use and schizophrenia on white-matter cerebellar volume loss [84]. However, another study found no differences in brain morphology between cannabis-using and non-using patients [85].

Among comorbid patients, Smith et al. [86•] examined the relationship of CUDs in at least 6 months of remission on subcortical brain structures in individuals with and without schizophrenia. Shape differences in the dorsal striatum, anterior thalamus, and anteriodorsal and ventral globus pallidus in patients with lifetime CUD were congruent with those observed among the cannabis-using controls; alterations were significantly more pronounced in cannabis-using patients compared with controls. Longitudinally, Rais and colleagues [87] examined the relationship between brain volume-loss over a 5-year interval in first-episode schizophrenia patients (n = 19) compared with non-using patients (n = 32). Cannabis-using patients demonstrated greater lateral and third ventricle enlargement and grey-matter loss compared with non-using patients and healthy controls.

Brain atrophy may be the consequence of abnormal brain developmental processes that occur during adolescence; thus, deficits are present even before the onset of schizophrenia and cannabis use. Brain volume loss may represent impairment in cortical inhibition and neuroplasticity, thereby adversely affecting maturation of neural circuitries within cortical areas. Reduced synapses, altered dendrites, and lack of generation of new neurons may result due to diminished glutamatergic neurotransmission [88]. Moreover, individuals who develop schizophrenia may be particularly sensitive to brain tissue loss on exposure to cannabis. Future studies should employ prospective designs to determine whether brain volume and white matter loss result in greater risk for using cannabis or whether continuous use of cannabis (versus non-use or abstinence) leads to excessive brain volume loss in schizophrenia.