Effect of Long-term Cannabis Use on Axonal Fibre Connectivity

Andrew Zalesky; Nadia Solowij; Murat Yücel; Dan I. Lubman; Michael Takagi; Ian H. Harding; Valentina Lorenzetti; Ruopeng Wang; Karissa Searle; Christos Pantelis; Marc Seal


Brain. 2012;135(7):2245-2255. 

In This Article

Abstract and Introduction


Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The aim of this study was to examine axonal fibre pathways across the brain for evidence of microstructural alterations associated with long-term cannabis use and to test whether age of regular cannabis use is associated with severity of any microstructural change. To this end, diffusion-weighted magnetic resonance imaging and brain connectivity mapping techniques were performed in 59 cannabis users with longstanding histories of heavy use and 33 matched controls. Axonal connectivity was found to be impaired in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum and commissural fibres. Radial and axial diffusivity in these pathways were associated with the age at which regular cannabis use commenced. Our findings indicate long-term cannabis use is hazardous to the white matter of the developing brain. Delaying the age at which regular use begins may minimize the severity of microstructural impairment.


The enduring neuropathological effects of long-term cannabis use are equivocal (Lorenzetti et al., 2010; Martin-Santos et al., 2010). Changes in tissue volume, morphology and composition have been reported in neuronal structures rich in cannabinoid receptors, most notably the hippocampus (Matochik et al., 2005; Medina et al., 2007; Yücel et al., 2008) and the cerebellum (Solowij et al., 2011b; Cohen et al., 2012). On the other hand, many studies have found no neuropathological effects (Block et al., 2000; Tzilos et al., 2005; Jager et al., 2007).

The discovery of cannabinoid receptors in oligodendroglial cells (Molina-Holgado et al., 2002) motivates a new line of investigation centred on white matter. In particular, cannabinoid receptors have been detected in white matter structures of the foetal and post-natal rat brain, including the corpus callosum, anterior commissure, fornix, stria terminalis and stria medullaris (Romero et al., 1997). In adulthood, the density of cannabinoid receptors in these fibre-enriched structures has been found to diminish, eventually supplanted by the classical distribution of cannabinoid receptors (Romero et al., 1997; Glass et al., 1998), which includes the cerebellum, hippocampus and caudate-putamen. This points to a transient developmental period during which white matter structures might be particularly sensitive to exogenous cannabis exposure (Fig. 1). More generally, developing white matter may be at greater risk of damage due to its higher concentration of cannabinoid receptors relative to the mature brain, an important consideration given adolescence and young adulthood is the peak time of cannabis initiation. Down regulation of the endogenous cannabinoid system due to long-term cannabis exposure during this developmental period (Dalton et al., 2010) may result in apoptosis of oligodendrocyte progenitors (Barres et al., 1992; Molina-Holgado et al., 2002) and thereby alter white matter development (Kumra, 2007; Solowij et al., 2011b).

Figure 1.

Unlike neuronal tissue, fibre-enriched structures become depleted of cannabinoid (CB) receptors as the rat brain matures. This leads to the hypothesis that axonal microstructure in the developing brain might be particularly reactive to exogenous cannabis exposure. Data extracted from Romero et al. (1997).

The aim of this study was to examine axonal fibre pathways in the human brain for evidence of microstructural alteration associated with long-term heavy cannabis use. It was hypothesized that the age when cannabis use became heavy and regular would be a factor determining the severity of any microstructural alteration.

To test this hypothesis, diffusion-weighted imaging, a MRI modality capable of elucidating axonal directionality and microstructure in vivo, was performed in 59 cannabis users with a history of longstanding, heavy use and 33 non-users. The diffusion-weighted imaging data were processed using a validated fibre tracking algorithm to create high-resolution white matter connectivity maps indicating the extent of axonal connectivity between thousands of distinct voxel pairs. A novel network-based statistic (Zalesky et al., 2010a) was then applied to isolate voxel pairs showing between-group connectivity differences. Measures of axonal microstructure were taken in axonal fibre pathways identified as aberrant and correlated with the age of regular cannabis use.

Few previous studies have used diffusion-weighted imaging techniques to investigate the enduring effects of cannabis use on white matter. Microstructural alteration in the corpus callosum (Arnone et al., 2008), the arcuate fasciculus (Ashtari et al., 2009) and white matter surrounding the hippocampus (Yücel et al., 2010) have been reported previously, while two studies found no effect on white matter (Gruber et al., 2005; Delisi et al., 2006). Two other studies have reported widespread white matter alterations in binge drinking cannabis users (Jacobus et al., 2009; Bava et al., 2010), while a recent graph-based study found reduced brain network efficiency and increased clustering in adult cannabis users (Kim et al., 2012). This study confers several key advantages over these prior studies. With 59 cannabis users, our sample size is substantially larger than the samples recruited in previous studies and is not confounded by concurrent alcohol abuse. Furthermore, unlike most of the previous studies that confined their investigations to predefined regions of interest, our data-driven strategy was not biased by a subjective choice of region of interest. These novel factors enabled us to precisely localize any axonal fibre pathways demonstrating microstructural alteration associated with long-term cannabis use.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: