Umræðukaflinn skrifaði:To our knowledge, this is the first study to investigate the effect of cannabis potency and frequency on CC WM microstructural organization, both in patients experiencing their first episode of psychosis and in cannabis users without psychosis. Our main finding, which is in line with our main hypothesis, is that frequent use of high-potency cannabis is significantly associated with altered callosal microstructural integrity. Furthermore, our results suggest that this particularly occurs in the most posterior part of the CC, including the splenium and the posterior mid-body. Interestingly, these alterations were similar in users with and without a psychotic disorder.
Our findings support a role for frequent use of high-potency cannabis in altered CC microstructure, suggesting that callosal integrity may be particularly sensitive to high THC concentration. CB1 receptors, on which THC acts, have a known effect on oligodendrocyte development (myelin initiation, deposition, compaction and maintenance) (Davis et al.2003). Hence, chronic or early exposure to high-THC cannabis preparations, compared with those with low THC, may alter WM through a down-regulation of CB1 receptors. This may result in apoptosis of oligodendrocyte progenitors during WM development (Walter et al.2003).
Although cannabis effects on WM have also been related to use that occurs early, when WM is still developing and cannabis receptors are abundant, we found no difference in WM integrity between individuals who started younger or older than 15 years of age. Still, considering that all our high-potency participants started using in their teens, and that WM continues to develop post-adolescence, it is possible that early adulthood remains a period of vulnerability. Indeed, one of the CC areas that we found to be most affected by frequent high-potency cannabis use was the splenium, which completes maturation only in young adulthood, and later than other callosal parts, thus remaining particularly susceptible to toxic effects of cannabis (De Bellis et al.2008). The splenium and the posterior mid-body, which we also found particularly affected, also contain motor fibres (Zarei et al.2006), and their alteration may contribute to a dysfunction of sensorimotor circuits, resulting in sensory perception alterations, impaired sensorimotor gating and hallucinations, all of which have been associated with cannabis abuse (Heng et al.2011).
While one should be cautious about interpreting DTI measures in terms of the pathological process that underlies microstructural changes, it is interesting that, similarly to other studies, we found that cannabis potency and frequency were associated with an increase in MD, but with no changes in FA. MD is a non-specific measure of integrity, and alterations in this measure can result from changes in intra- or extra-cellular space, including extra-cellular oedema, and therefore be temporary and reversible (Bosch et al.2012). Increases in MD are also observed in pathologies accompanied by neuropil reduction and may reflect demyelination or axonal loss (Selemon et al.1999). Cannabis frequency and potency were also associated with an increase in AD and, at trend level, RD. It is possible that neurobiological changes such as fibre reorganization, glial alteration and even axonal degeneration induce water to diffuse in unanticipated directions and therefore increase measures such as AD (Beaulieu et al.2002). The concordance of changes in tensor metrics, with increases in MD, AD and RD, can also lead to proportional non-significant changes in FA, as the ones seen in our study and similar to those observed in other neurological disorders such as Alzheimer's disease (Acosta-Cabronero et al.2010).
We were somewhat surprised to see that differences in callosal integrity in relation to cannabis potency were larger in the individuals without psychosis than in the patients. Comparison with other structural neuroimaging studies of cannabis use in FEP patients is difficult as only three studies to date have used DTI and none has examined patterns of cannabis use. Dekker et al. (2010) found reduced callosal FA in a small sample of eight cannabis-naive patients with schizophrenia compared with 10 early-user patients, and no morphological differences between early-onset and late-onset cannabis users with schizophrenia. Unfortunately, the study did not report MD or AD values. In contrast, James et al. (2011) found that early cannabis use in adolescent-onset schizophrenia was associated with lower FA in the brain stem, internal capsule, corona radiata, and superior and inferior longitudinal fasciculi. Finally, a recent study in FEP patients found no brain-wide differences in grey matter or WM between lifetime heavy and light users, or non-users (Haller et al.2013). Several methodological differences may explain these inconsistencies. For example, most studies used small samples, and subjects varied in age range and diagnosis, with most including only patients with schizophrenia rather than all psychoses. Also, the methods used to examine WM differ across studies. These factors potentially affect all neuroimaging investigations and make it difficult to extrapolate whether differences in findings are due to sample characteristics or methods used. Still, it is possible that the alterations in WM microstructure we detected in our early, high-potency cannabis-user patients would become even more significant if a larger sample is examined. Of note, we did not find differences in the proportion of cannabis users and the related patterns of use across diagnostic groups. This is an important clinical issue and a study with a larger sample size would allow a more specific evaluation of the role of diagnosis in relation to pattern of cannabis use and brain structure in psychosis.
Our data go further than previous evidence and suggest that cannabis potency and frequency affect the CC in individuals with and without psychosis, and possibly reflect a subtle and general effect rather than altered neuronal integrity. This is consistent with evidence of callosal alterations in non-psychotic long-term and heavy cannabis users (Arnone et al.2008; Zalesky et al.2012). Overall, the finding is even more interesting when we consider that on direct comparison, our patients had significantly lower callosal FA values than individuals without psychosis, suggesting that: (a) our patients have alterations similar to those previously reported in psychosis samples (Lener et al.2015); and (b) that this was apparent even though our individuals without psychosis included cannabis users.
This study has a number of strengths. We have evaluated the role of cannabis potency in relation to brain structure for the first time. Furthermore, we have used a sample larger than those used in previous studies, and evaluated users both with and without psychosis. This has allowed us to provide data on the effects of cannabis potency and pattern of use independently of the presence of psychosis. In addition, all our patients were at their first psychotic episode. Therefore, cannabis use had occurred prior to (or around) illness onset, and not as a consequence of the illness. Also, patients were not exposed to long-term pharmacological treatment, making it unlikely that WM alterations were due to antipsychotic medications. Finally, we used a reliable and comprehensive fibre-tracking method for the evaluation of the CC, which has additionally provided details on the integrity of its subsections.
Although our sample is one of the largest in which WM and cannabis use have been evaluated, the number of subjects using low-potency cannabis was relatively small. This may actually reflect the shift that has occurred in the UK towards use of more high-potency cannabis, which also reassures us that participants were more likely to admit to their use. The lack of objective measures of cannabis use is another important limitation. However, other studies that have used self-report measures have also shown an association with brain structural alterations (Yücel et al.2008; Cousijn et al.2012). The fact that many of the individuals without psychosis admitted to their cannabis use also gives us confidence that participants were honest and open about their pattern of use. Nevertheless, in a random sample of 56 cases from the original sample, we carried out a urine drug screen to test the reliability of data on current use (up to 4 weeks prior to the assessment). Of the 56 cases tested, 34 had reported they were not current users; 32 of these (94%) had a negative urinary drug screening; only two tested positive (Di Forti et al.2012). In addition, there is published evidence indicating that asking patients with psychosis and individuals from the general population about their use of cannabis is, at least in some situations, more accurate than, or as reliable as, urine or blood testing which can only provide information on recent use (Hjorthøj et al.2011; Freeman et al.2014). Finally, the accuracy of the neuroimaging approach we used is contingent on its reliability, and tensorial tractography models such as those used in this study fail to map multiple fibre orientations in one voxel, and therefore may fail to map the fibres of the CC lateral to the crossing with the cortico-spinal tract. Tractography nevertheless uses information from a larger part of the tract than either voxel-based or tract-based spatial statistics (TBSS) methods of analysis and may therefore be preferable (Dell'Acqua et al.2013).
This study provides the first report that WM disarray is greater among heavy users of high-potency cannabis, than in occasional or low-potency users, and that this is independent of the presence of a psychotic disorder. Unfortunately, high-potency cannabis is replacing traditional herbal cannabis preparations in many European countries. Raising awareness about the risks of high-potency cannabis abuse seems therefore crucial. It will be extremely important that future studies evaluating the effects of cannabis use on brain structure and function include a careful assessment of cannabis potency.
