Long-Term Effects of Cannabis on Brain Structure, Giovanni Battistella et al., 2014

Long-Term Effects of Cannabis on Brain Structure

Giovanni Battistella, Eleonora Fornari, Jean-Marie Annoni, Haithem Chtioui, Kim Dao,
Marie Fabritius, Bernard Favrat, Jean-Frederic Mall, Philippe Maeder and Christian Giroud

Neuropsychopharmacology, 2014, 39, 2041–2048.




The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.



Cannabis is one of the most widely used recreational drugs, taking third place among drugs of concern in addiction treatment services (Degenhardt et al, 2008). Despite these statistics pointing to the potential harms associated with longterm cannabis use, little is known about the progression from recreational to regular use and its effects on brain structure.

Current knowledge is mostly inferred from animal studies; it has been demonstrated that the main psychoactive component of cannabis (D9-Tetrahydrocannabinol, THC) induces dose-dependent toxicity and structural changes in brain regions rich in cannabinoid CB1 receptors. These are mainly located in the hippocampus, amygdala, cerebellum, prefrontal cortex, and striatum (Burns et al, 2007; Downer et al, 2001; Lawston et al, 2000).

In contrast to the animal literature, the investigation of the structural effects of long-term cannabis use on the human brain has brought less consistent findings. Changes in gray or white matter density have been reported in different locations in frontal and parietal lobes without overlapping findings across studies (Churchwell et al, 2010; Gruber et al, 2011; Matochik et al, 2005). The discrepancy in the results might be due to heterogeneity in sample characteristics, inter-individual differences linked to past
history of drug use, amount of consumption, related psychological problems (temperament, level of anxiety or arousal), and/or methodological differences in data processing (Batalla et al, 2013; Lorenzetti et al, 2010). However, changes in the hippocampus/parahippocampal complex and in the amygdala have often been reported (Demirakca et al, 2011; Matochik et al, 2005; Yu¨cel et al, 2008; Zalesky et al, 2012). These findings suggest that long-term cannabis use is associated with brain morphology alterations in regions linked to memory and executive and affective processing (Yu¨cel et al, 2008).

Decrease in hippocampal volume in regular cannabis smokers has been correlated with lifetime consumption (Ashtari et al, 2011; Yu¨cel et al, 2008) and psychotic symptoms (Yu¨cel et al, 2008). In Cousijn et al (2012), volume reduction in the amygdala and the hippocampus does not differ significantly between regular cannabis users and controls but still correlates with the amount of cannabis used and the severity of cannabis dependence, respectively.

In addition to the several issues characterizing the literature so far, most of the studies examine only predefined regions of interest (i.e., the hippocampus and amygdala because of their richness in CB1 receptors), making it difficult to draw consistent and complete conclusions about the long-term effects of cannabis use on brain structure.

Another question of interest is whether cannabis use is associated with differential effects on brain structure according to the age of consumption onset; more specifically, does the use of cannabis during adolescence lead to the same changes in brain structure as initial exposure later in life? Adolescence is an important period in brain development when proper structural maturation of fiber tracts occurs (necessary for the development of cognitive, motor, and sensory functions) (Paus et al, 1999). Environmental factors, such as drug use, can alter the maturational arrangements that normally occur in the adolescent brain (Hurd et al, 2013), increasing the incidence of psychiatric illness and substance abuse (Paus et al, 2008). The study by Zalesky et al (2012) shows a linear correlation between measures of white matter (WM) integrity and the age of onset of regular cannabis use, thus suggesting a toxic effect
of long-term cannabis use to WM development.

In our study, we investigate the precise nature of structural changes induced by cannabis and try to answer three main questions: (i) Can we observe temporal and frontal (including insular) gray matter changes after long-term exposure to cannabis? (ii) Is the magnitude of these changes related to the amount of cannabis consumed? (iii) Are these changes influenced by the age of first use (during/after adolescence)?

Unlike many previous studies, we used a whole-brain voxel-wise approach in order to localize gray matter change due to long-term exposure to cannabis. To this end, we used Voxel-based Morphometry (VBM), a completely automatic and unbiased data processing technique for the assessment of gray matter density. This technique has been already widely used in clinical research (Draganski and Bhatia,
2010) and in drug addiction (Connolly et al, 2013).

Brain structure changes were investigated in a group of regular cannabis smokers and compared with a group of occasional smokers enrolled in our previous functional study (Battistella et al, 2013). The subjects in the two groups did not use any drug other than cannabis and were free from psychiatric disorders. We then stratified the two groups according to the age of first cannabis use in order to assess the effect of cannabis on the developing brain.