Our study demonstrates a pattern of gray matter volume changes in a group of regular cannabis users compared with a group of occasional ones. Regular users exhibit a decrease in gray matter (GM) volume in the medial temporal cortex, temporal pole, parahippocampal gyrus, left insula, and orbitofrontal cortex. These changes strongly correlate with the monthly frequency of cannabis use in the 3 months before inclusion in the study. We chose the preceding 3-month period as the period of interest because the participants’ cannabis use during this length of time is representative of their usual cannabis use. Three clusters in the cerebellum show the opposite behavior, with increased GM volume. We also show that the age of onset of cannabis use is correlated with the magnitude of gray matter volume reduction in the cerebral hemispheres. Specifically, significant gray matter atrophy can occur either with a heavy cannabis consumption independent of the age of first use or with recreational consumption that started during adolescence (before the age of 18).

Our finding corroborates several animal studies (Burns et al, 2007; Downer et al, 2001; Lawston et al, 2000), adding evidence that the duration of exposure to cannabis is indeed associated with localized volume reduction in regions rich in CB1 receptors, correlating with the amount of cannabis used.

The progression of a long-term exposure to drugs toward the development of substance use disorders and addicted behaviors is often associated with deficits in decision making (Koob and Volkow, 2010; Wiers et al, 2007). FMRI demonstrates altered brain activity in core regions linked to the motivational and affective aspects of decision making (Cousijn et al, 2012; Vaidya et al, 2012), mainly in the ventromedial prefrontal (VMPFC) and orbitofrontal cortices and insula. In this regard, it has been demonstrated that substance-dependent individuals and patients with VMPFC lesions exhibit similar behaviors that lead them to make similar decisions in real life, preferring choices that bring immediate benefits even if coupled with negative consequences (Bechara and Damasio, 2002).

In our study, we complement the functional evidence of altered activity in nodes related to decision making by showing in regular cannabis users a decrease in gray matter volume in the insula, orbitofrontal cortex, and precuneus, regions that are part of the motivational and affective components of this network.

This observation supports and extends the conclusions about compromised activity in the Salience Network nodes (Seeley et al, 2007) described in occasional cannabis users following the smoking of a single joint of cannabis (Battistella et al, 2013). The key role in this network is played by the insula, a region involved in subjects’ awareness of error, in the processing of affective and internal information and in switching between the different brain networks. Changes in this structure have also been confirmed in alcohol addiction where the decrease in insular activation seems to reflect an inability to switch from interoceptive cravings to cognitive control for suppressing internal needs (Sullivan et al, 2013). Here we complement this finding of functional change with its structural substrate. On the other hand, the activity in other nodes of the Salience and the Control Executive networks (VMPFC, ACC, Dorsolateral Prefrontal cortex) that is compromised in occasional smokers is not associated with structural changes in these regions in regular cannabis smokers. It remains thus to be explored whether morphological variations in these areas may occur at a later stage or in the presence of more serious addiction-related behaviors that our participants do not exhibit.

In relation to gray matter volume reduction in regions linked to affective and emotional processes described so far (the insula and the orbitofrontal cortex), we also show structural variations in the temporal pole (TP). The TP shares cytoarchitectural and functional characteristics with the orbitofrontal cortex (Kling and Steklis, 1976) and receives projections from the insula. The volume reduction in these regions observed in our population supports the idea of a joint role of these structures in regular cannabis use. Evidence exists about the role of the temporal pole (TP) in coupling emotions and highly processed sensory stimuli (Olson et al, 2007). Lesions in this structure lead to changes in personality and in social behavior (Thompson et al, 2003). Ablation of the monkey orbitofrontal cortex, TP, and amygdala causes similar socioemotional deficits. To our knowledge, ours is the first study showing gray matter atrophy in the temporal pole in regular cannabis users and the degree of atrophy related to the frequency of drug use in the 3 months preceding inclusion in the study. Previous research using ROI analysis did not focus on possible changes in this region. With regard to the two studies using VBM, one (Matochik et al, 2005) found changes only in the medial part of the temporal cortex, maybe due to the small sample studied; the other (Cousijn et al, 2012) failed to find any change in the cerebral cortex. Atrophy of this structure has been found in cocaine users (Albein-Urios et al, 2013) and has been linked to socioemotional and personality problems.

In addition to the changes in the polar regions, there are also changes in the medial temporal cortex, which is one of the structures often reported to be associated with cannabis addiction and where we find a strong bilateral decrease in gray matter volume in the population of regular cannabis users. Such a pattern of atrophy has been also described in other forms of addiction such as alcohol addiction (Mechtcheriakov et al, 2007), but not in heroin users (Denier et al, 2013). However, other patients with severe, non-toxic, behavioral addiction such as pathological gambling (Levine et al, 2005) do not present the same form of atrophy, suggesting that temporal atrophy is indeed associated with cannabis consumption rather than with addictive behavior itself. Despite the fact that the neurobiological interpretation of this volume reduction is still unclear, studies on rodents give some clues on this point. Scallet et al (1987) found a THC-induced decrease in the mean volume of hippocampal neurons and a 44% reduction in the number of synapses up to 7 months after exposure. Functional and structural variations in the hippocampus have been linked to reduced memory performance (Solowij and Battisti, 2008) and psychotic symptoms (Yücel et al, 2008). Cannabis exposure produces reduced activation in the hippocampus during verbal and visual learning tasks (Block et al, 2002; Jager et al, 2007).

Another main finding of our study is the increase in gray matter volume in the cerebellum that replicates results in adults (Cousijn et al, 2012) and in adolescents (Medina et al, 2010).

In normal adolescents the volume of cerebellar gray matter starts to decrease around puberty and continues until early adulthood (Diamond, 2000; Ostby et al, 2009). Alterations of this phenomenon have been observed in various psychiatric conditions (Mackie et al, 2007) (Jarvis et al, 2008) (Castellanos et al, 2002) (Pujol et al, 2004) (Hill et al, 2003) and in adolescents with familiar history of severe alcohol abuse (Hill et al, 2007).

It has been hypothesized that this normal reduction in gray matter volume in the cerebellum is due to the pruning of the synaptic connections (Cohen-Cory, 2002). One possible reason for abnormal pruning could be the toxic effect of THC at a critical period of brain maturation. Endogenous cannabinoids have an important role in synaptic pruning due to their interaction with GB1 receptors controlling the release of glutamate and GABA (Bossong and Niesink, 2010). Exogenous cannabinoids might disturb this system by competing for the receptors, thus inhibiting the pruning particularly in receptor-rich areas like the cerebellum (Casu et al, 2005) or the prefrontal cortex (Bossong and Niesink, 2010).

However, our results cannot exclude that abnormal pruning is due to genetic predisposition as seen in children from multiplex alcoholic families even before the beginning of any drinking behavior or in obsessive compulsive disorder (Hill et al, 2007). Hence, a limitation of our study and a matter of debate in the literature are connected to the question of whether these brain changes are caused by cannabis use or are already present before drug use.

Additional limitation of our study is the relatively narrow age-range of our participants (19–29 years of age) that may limit the possibility to totally capture the cumulative effects of cannabis. On the other hand, a 10-year window of age range assures the homogeneity of the two groups, aspect of paramount importance in the context of group analysis.

Existing literature shows that cognitive alterations and CB1 receptor downregulation in regular cannabis users may return to normal values due to neuroadaptive phenomena occurring after periods of abstinence (Bosker et al, 2013; Hanson et al, 2010; Hirvonen et al, 2012; Schweinsburg et al, 2010). The design of our study cannot address whether the structural alterations observed are permanent or reversible. The so far unexplored evolution of the gray matter alterations across time and the possible recovery after recency of use should be addressed by further longitudinal studies.

In our study, we provide new arguments about the effects of long-term exposure to cannabis on brain structure integrity. We were able to support all the hypotheses raised in the introduction: (i) we demonstrate that regular cannabis use is associated with reduced gray matter volume in regions rich in cannabinoid CB1 receptors that are functionally linked to motivational, emotional, and affective processing. (ii) We complete our findings by showing that the magnitude of changes in these regions correlates with the frequency of cannabis use and (iii) is modulated by the age at which consumption was initiated.

We present a different scenario in the cerebellum where the increase in gray matter volume in regular users without any correlation with the amount of cannabis use may have a developmental nature. The line of research should move toward longitudinal studies in order to differentiate between consumption-related and developmental aspects of brain changes associated with long-term regular cannabis exposure.