The existing literature on the long-term effects of marijuana on the brain provides an inconsistent picture due to methodological differences across studies. We overcame these methodological issues by collecting multimodal measures in a large group of chronic marijuana using adults with a wide age range that allows for characterization of changes across lifespan without developmental or maturational biases as in other studies. Our findings suggest that chronic marijuana use is associated with complex neuroadaptive processes and that onset and duration of use have unique effects on these processes. Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and sex nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana studies and use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

The rate of cannabis use has had a steady increase since 2007. THC binds to cannabinoid receptors, which are ubiquitous in the brain. Consequently, exposure to THC leads to neural changes affecting diverse cognitive processes. These changes have been observed to be long-lasting, suggesting that neural changes due to cannabis use may affect neural architecture (2). However, to date, these brain changes as a result of marijuana use remains equivocal. Specifically, although functional changes have been widely reported across cognitive domains in both adult and adolescent cannabis users, structural changes associated with marijuana use have not been consistent. Although some have reported decreases in regional brain volume such as in the hippocampus, orbitofrontal cortex, amygdala, and striatum, others have reported increases in amygdala, nucleus accumbens, and cerebellar volumes in chronic marijuana users. However, others have reported no observable difference in global or regional gray or white matter volumes in chronic marijuana users. These inconsistencies could be attributed to methodological differences across studies pertaining to study samples (e.g., severity of marijuana use, age, sex, comorbidity with other substance use or psychiatric disorders) and/or study design.

Because THC binds to cannabinoid 1 (CB1) receptors in the brain, when differences are observed, these morphological changes associated with marijuana use have been reported in CB1 receptor-enriched areas such as the orbitofrontal cortex, anterior cingulate, striatum, amygdala, insula, hippocampus, and cerebellum. CB1 receptors are widely distributed in the neocortex, but more restricted in the hindbrain and the spinal cord. For example, in a recent study by Battistella et al., they found significant brain volume reductions in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex (OFC) in regular marijuana users compared with occasional users. Whether these reductions in brain volume lead to downstream changes in brain organization and function, however, is still unknown.

Nevertheless, emergent studies have demonstrated a link between brain structure and connectivity. For example, demonstrated robust structural connections between white matter indexes and functional connectivity strength within the default mode network. Similarly, others have reported correlated patterns of gray matter structure and connectivity that are in many ways reflective of the underlying intrinsic networks. Thus, given the literature suggesting a direct relationship between structural and functional connectivity, it is likely that connectivity changes would also be present where alterations in brain volume are observed as a result of marijuana use.

The goal of this study was to characterize alterations in brain morphometry and determine potential downstream effects in connectivity as a result of chronic marijuana use. To address the existing inconsistencies in the literature that may be in part due to methodological issues, we used three different MRI techniques to investigate a large cohort of well-characterized chronic cannabis users with a wide age range (allowing for characterization without developmental or maturational biases and compared them to age and sexmatched nonusing controls examined observable global rather than select) gray matter differences between marijuana users and nonusing controls and performed subsequent analyses to determine how these changes relate to functional and structural connectivity, as well as behavior. Given the existing literature on morphometric reductions associated with long-term marijuana use, we expected gray matter reductions in THC-enriched areas in chronic marijuana users that will be associated with changes in brain connectivity and marijuana-related behavior.