Brain Morphology of Cannabis Users With or Without Psychosis: A Pilot MRI Study

In the present study, we observed that only the presence of psychotic symptoms discriminated the detection of brain morphological alterations. Indeed, chronic cannabis users with CIP showed decreased GM volumes mainly in the prefronto-temporo-limbic network compared to non-psychotic cannabis users (NPCU). Moreover, regarding the psychometric questionnaires, correlations between the domain BPRS-Activity and selective GM volumes have been highlighted. Specifically, we observed a negative correlation between such BPRS scale and left superior temporal cortex and left cerebellum together with a positive correlation with the cuneus bilaterally, the left inferior occipital gyrus, the right inferior parietal lobule and the right superior prefrontal cortex. However, we should mention that the lack of a control group of healthy subjects with no cannabis dependency prevented us from exploring if cannabis use caused brain alterations or not.

In general, the results are not surprising since previous MRI studies showed that psychotic disorders, such as schizophrenia, shared similar GM abnormalities, especially in frontal and temporo-limbic regions^29,30. However, it is still unclear why some chronic cannabis users developed psychotic symptoms while others remained healthy. Indeed, in the sample, we only detected small clinical differences between the two groups and therefore the extensive GM abnormalities observed in the CIP group may not be associated with their specific clinical profile. Specifically, 9 of 10 CIP patients reported a daily cannabis use compared to 7 of 12 in the NPCU group. Moreover, no differences in terms of age, gender, age of onset of cannabis use and educational level were found between the two groups. However, we should consider that this lack of differences could be due to the small sample size that also limited the possibility to statistically analyse and interpret these factors. One hypothesis is that the psychotic process itself is responsible for the decrease in brain volume, regardless cannabis use. Indeed, previous studies showed no GM differences between psychotic patients with and without cannabis consumption, thus finding no clear evidence for cannabis use to be related to GM alterations in first episode psychotic patients⁴⁵. However, cannabis use may have contributed to brain alterations and subsequently induced psychosis only in a subgroup of susceptible cannabis users.

The first hypothesis is in line with those studies showing brain abnormalities in psychotic disorders. Specifically, the results showed that CIP patients compared to NPCU had extensive GM volume decreases in some brain areas known to be involved in emotional regulation, such as frontotemporal cortices, insula, hippocampus, and fusiform gyrus⁴⁶. Interestingly, disruptions in these structures, especially in prefrontal regions, might explain the mood instability and greater emotional reactivity in adolescents and young adults, as well as impulsive behaviors and substance-seeking^33,34. Indeed, it has been consistently reported that emotion regulation/processing are associated with recruitment of a set of prefrontal brain regions involved in cognitive control over emotional limbic structures. For example, greater difficulties in emotional regulation among tobacco smokers have been associated to a weaker connectivity between inferior frontal gyrus and amygdala compared to non-smokers⁴⁹. Therefore, it might be plausible that among CIP patients the development of psychotic symptoms was associated with interfered balance between these structures.

Additionally, we observed that the group of CIP patients showed disruptions in the dorsolateral prefrontal cortex (DLPFC), a key region involved in major cognitive functions, including working memory, executive functions⁵⁰ and emotional regulation⁵¹. Indeed, this finding is not surprising since the DLPFC works together with risk-monitoring regions, such as the insula (a key structure of the salience network recently found to be involved in addiction⁵²⁾, which has been also found altered in the group of CIP patients, and anterior cingulate cortex, ultimately suggesting that impairments in distinguishing risky from safe choices may result from a disruption between DLPFC and such risk-monitoring regions⁵³.

Moreover, CIP patients showed a GM volume decrease in the superior temporal cortex. Interestingly, this result is in line with the evidence reported by a previous multimodal neuroimaging study⁵⁴, which employed a larger sample of CIP patients (N=16), the majority of whom overlap with the sample employed in this study that found extensive GM alteration in temporal cortices in CIP patients. Overall such evidence further confirms the key role of the superior temporal cortex in psychosis, since the involvement of this structure has been consistently reported in abilities often found disrupted in psychotic patients, including language processing and theory of mind abilities^39,40. Also, the results aligned with previous evidence reporting the association between volume reductions of this region and auditory hallucination or thought disorders^41,42 as well as with a previous MRI study suggesting the disruption of this area in substance dependent individuals compared to healthy controls⁵⁹.

Finally, a significant GM volume decrease in hippocampus in CIP patients emerged from the results. Such finding is in line with previous evidence showing structural and functional changes in this structure in early psychoses and in at-risk mental state/first-episode psychosis, in comparison to healthy controls^60,61,62,63. Normal hippocampal function is required for a number of mental functions including memory and emotional behaviour^48,49 and it has been proposed that reduced volume in this structure may represent a marker of a negative clinical outcome in patients with a first-episode psychosis⁶⁶. However, in contrast to the results, hippocampal deficits have been also reported in young and adult cannabis users, who have been found to have thinner cortices and reduced volumes in this region^67,68,69,70. Therefore, a clear picture on the role of the hippocampus in substance abuse has still not be attained. Nonetheless, the results point towards the hypothesis that the cortico-limbic system is compromised in the group of CIP patients, as also suggested by a previous MRI study⁵⁴ and might explain the emotional elaboration deficits, which has been proposed to be a critical precursor of future psychotic development^55,56, often observed in these patients.

Therefore, it seems reasonable to hypothesize that cannabis-induced psychosis is associated with brain alterations in regions within the prefronto-temporo-limbic network, which may therefore represent a common neurodevelopmental substrate of multiple forms of psychosis. Interestingly, longitudinal studies proposed that some brain disruptions, including smaller orbitofrontal cortex volumes⁷³, increased fronto-parietal and decreased visual association regions activation, as well as cognitive deficits, such as poorer executive functions⁷⁴, may be present even before the initiation of cannabis dependency. Therefore, it might be that these individuals with underlying brain alterations are more likely to develop psychotic symptoms after cannabis use initiation. In addition, there is evidence reporting that possessing risk alleles in AKT1 and DRD2 genes, which are involved in dopamine signalling, is associated with increased risk of developing psychosis after cannabis use³. Therefore, the detection of morphological decreases in CIP patients could reflect an augmented genetic susceptibility to the neurotoxic effect of chronic cannabis use in this group of subjects.

Finally, in the CIP group, the results also showed a negative correlation between a sub-domain of the BPRS, the BPRS-Activity, and selective GM volumes within left superior temporal cortex and left cerebellum. Also, this subscale was positively correlated with cuneus bilaterally, left inferior occipital gyrus, right inferior parietal lobule, and right superior prefrontal cortex. In general, although correlations between clinical symptomatology and GM structures have been extensively reported, especially in schizophrenia⁷⁵, the results are still heterogeneous, with a mixed picture of inverse⁷⁶, positive⁷⁷ or no⁷⁸ correlations between selective GM volumes and clinical scales. Notably, the negative correlation observed between BPRS-Activity and superior temporal cortex seems to be in line with previous MRI evidence showing inverse correlations between this structure and positive symptom severity⁷⁶, ultimately further suggesting the key role of this structure in the production of psychotic symptoms. Similarly, the positive correlation found between BPRS-Activity and superior prefrontal cortex seems to agree with other MRI studies reporting a similar correlation between negative symptoms and GM volumes with the prefrontal cortex⁷⁹.

As a whole, the results of the current study provide preliminary evidence on the presence of significant association between brain alteration and severity of psychopathology.

The current study suffers from some limitations. First, all psychotic patients were taking pharmacological treatments that could have influenced the results. Second, the lack of a control group formed by healthy subjects not exposed to cannabis does not allow a further comparison with the two groups of cannabis users (psychotic and not). In addition, although the two groups were very similar in terms of number of subjects (10 CIP patients vs 12 NPCU), the small sample size limits the significance of the results achieved and therefore must be considered as preliminary. Further limitations are strictly connected to the nature of the population investigated. Indeed, some patients with CIP (6/10) and a rather small proportion of NPCU (3/12) had a lifetime history of other substance consumption (i.e., cocaine, LSD and heroin/methadone). Moreover, we did not examine the genetic alleles linked to addiction, which could have helped to discriminate the two groups. Nonetheless, the cannabis consumption, although assessed in terms of frequency and volume and duration with a specific tool²⁰, was not uniform across the two groups. Finally, in this study we did not explore brain activation and we did not assess the neurocognitive state of the sample. Therefore, the lack of these information could have affected the results since previous studies demonstrated the presence of selective brain dysfunctions in patients with schizophrenia with substance abuse in the medial prefrontal cortex, the orbitofrontal cortex and the amygdala as well as a better premorbid neurocognitive profile with a greater long-term decline compared to the same patients without substance abuse⁸⁰. Therefore, further functional MRI studies exploring brain activity coupled with neuropsychological assessments on larger samples and with homogenous consumption habits are needed to confirm our results.

According to our results, cannabis-induced psychosis may be characterized by GM volume decreases in selective brain structures. Therefore, in view of the crucial and comprehensive role of the endocannabinoid system in the brain, the increasing prevalence of cannabis use, its chronic use during neurodevelopment, as well as the progressively higher THC concentration in the current market, it seems mandatory to clarify which aspects of cannabis exposure (e.g., age at initiation, quantity, frequency, and duration) determine the greatest risk for the progression towards psychotic-related disorders. However, whether reductions in prefronto-temporo-limbic regions represent a substrate of the psychotic process itself or a direct consequence of cannabis exposure among susceptible subjects remains a complex issue. In this context, the methods employed in the study could be useful to better characterize the neurobiological and clinical features of cannabis-induced psychosis. Finally, longitudinal neuroimaging studies taking into account also potential confounding factors, such as cannabis dose, potency, THC/Cannabidiol ratio, frequency of use, age of onset, familiar history of psychosis, and genetic polymorphisms may provide a potential ground for identifying putative biomarkers which may ultimately help clinicians to detect those cannabis users that are more likely to develop psychosis.