As hypothesized, we found significantly reduced FA in both left and right genu of the corpus callosum and significantly higher BIS scores for the MJ smokers relative to the non-MJ-smoking control participants. Correlation analyses revealed a significant relationship between the age of MJ onset and FA in both the left and right genu, suggesting that earlier onset of MJ use is associated with lower white matter fiber tract integrity in these brain regions. Further, while BIS scores were inversely correlated with FA in the MJ smokers, with lower levels of FA associated with higher levels of reported impulsivity, this relationship was driven primarily by the early onset smoking group; higher impulsivity scores were significantly associated with lower FA in both the left and right genu of early onset smokers. In the aggregate, these data suggest that a specific relationship exists between FA and behavioral impulsivity in those who begin smoking MJ prior to the age of 16.

Data from the present study are consistent with previous studies of white matter microstructure in MJ smokers (Arnone et al. 2008; Ashtari et al. 2009; Bava et al. 2009; Jacobus et al. 2009a, 2009b), as well as studies that have independently examined impulsivity in substance-abusing populations (Vangsness et al. 2005; Johnson et al. 2010). Specifically, previous studies have reported decreased FA, as well as higher levels of behavioral impulsivity in MJ smokers. Results from a recent study of the effects of MJ use on white matter integrity suggest that impaired axonal connectivity exists in several regions of the corpus callosum in heavy MJ users (Zalesky et al. 2012). In addition, the authors report that age of onset of MJ was a significant factor in determining the severity of microstructural alteration; both radial and axial diffusivity were correlated with age of MJ onset. The relationship noted between altered white matter measures and age of onset may be the result of the development of white matter in the adolescent brain. During these years, age appropriate myelination is represented by progressive increases in FA and decreases in mean diffusivity (Morriss et al. 1999), which occurs in parallel with the process of cognitive development, most notably improvements in executive function. Early exposure to MJ during a vulnerable period of development may therefore result in lasting morphologic changes as evidenced in animal (Cha et al. 2006; Schneider and Koch, 2003) and human (Yucel et al. 2008; Mata et al. 2010) studies.

Recent investigations also lend support to our finding of increased behavioral impulsivity in MJ smokers. Dougherty et al. (2013) reported significantly higher BIS scores in adolescent MJ smokers relative to non-MJ-smoking controls. Further, MJ smokers demonstrated deficits in several neurocognitive domains, including those related to impulse control. Difficulty with inhibition and impulse control are likely to have consequences in the daily lives of MJ smokers, and in fact, results of a recent study of MJ-related problems in frequent users revealed that higher trait impulsivity scores predicted a greater number of problems in MJ users, most commonly procrastination and lower energy levels (Day et al. 2013).

While several studies have independently investigated white matter alterations and impulsivity, the current study was focused on the specific association between alterations in white matter microstructure and impulsivity in MJ smokers, a relationship previously detected in other substance-abusing populations, including cocaine-dependent subjects (Moeller et al. 2005) and methamphetamine abusers (Salo et al. 2009). Further, the current investigation analyzed the impact of age of onset of MJ use on these variables, which revealed that decreased white matter integrity is associated with higher levels of impulsivity, specifically among individuals who initiated MJ use prior to age 16. This specific relationship, noted primarily in the early onset smokers, is perhaps related to the changing distribution of cannabinoid receptors, which occurs throughout the normal trajectory of white matter development during adolescence. Research in both animals and humans has suggested that the developing nervous system contains an abundance of cannabinoid receptors in neural fiber tracts, which diminishes over time and becomes redistributed heterogeneously throughout the adult brain (Romero et al. 1997; Glass et al. 1998). Higher concentrations of cannabinoid receptors in neural fiber tracts during adolescence may therefore represent a period of specific vulnerability to the effects of MJ use on white matter microstructure, which is of particular concern given the importance of frontal regions for the successful completion of tasks requiring cognitive control and inhibition. In a recent study of healthy children aged 7–9, Chaddock-Heyman et al. (2013) found a significant relationship between greater white matter integrity and better performance on trials of a task requiring cognitive control. It is not surprising, therefore, that chronic, heavy MJ smokers, specifically those who began smoking prior to age 16, have been shown to exhibit both white matter alterations and a compromised ability to inhibit inappropriate responses on cognitive measures (Gruber et al. 2012a).

The current finding of higher reported impulsivity scores which are associated with white matter alterations in MJ smokers may also be related to the crossing of fibers through the genu, connecting the left and right dorsolateral prefrontal cortex (DLPFC), which has strong interconnections to the anterior cingulate cortex (ACC; Pandya and Seltzer 1982; Park et al. 2008). Both the ACC and DLPFC are components of the cingulo-fronto-parietal cognitive attention network, which is implicated in executive control, inhibition, attention, and feedback-based decision making (Bush et al. 2008). Decreased FA in the genu of MJ smokers relative to control participants may therefore alter this network, resulting in the difficulties observed in MJ smokers with impulse control. This network may also be particularly susceptible to the effects of long-term exposure of MJ, as the fibers within the genu are thinner than those in other regions, such as the splenium (Aboitiz et al. 1996).

Limitations

While findings from this investigation are compelling, a number of limitations should be noted. The current study included a limited sample size, and future studies should expand research in this area by utilizing larger study samples. Further, in the current study, a few individuals in both the MJ-smoking and healthy comparison group reported having used cigarettes, albeit at extremely low levels. Given the potential impact of cigarette smoking on brain structure, future studies should include only individuals who are naïve to cigarette or nicotine use. It is of note that no significant differences in FTND scores or in the number of individuals who used smoked cigarettes or used nicotine (past or present) were detected between the groups in the current study, making it unlikely that the between differences were impacted by cigarettes or nicotine. However, given the fact that slightly more MJ smokers smoked cigarettes than healthy control subjects (although this difference was not statistically significant), and that recent research has shown higher FA in cigarette smokers relative to nonsmokers (Jacobsen et al. 2007; Paul et al. 2008; Hudkins et al. 2012), the inclusion of infrequent cigarette smokers in the currently investigation likely only would have underestimated between group differences in FA.

In addition, previous studies, including our own (Gruber et al. 2011b), have reported frontal white matter alterations in MJ smokers. Although the current study reports decreased FA in MJ smokers and is consistent with our previous work in this area, we previously reported a positive correlation between BIS scores and frontal FA. It is of note, however, that the previous investigation included a more limited DTI scheme, acquiring data from only six directions, and only a subset of subjects (N = 10) had completed both the BIS and DTI measures. In contrast, the present study utilized a more comprehensive DTI acquisition method (48 directions), advanced standardized analytic techniques (TBSS), and a significantly larger sample size, which provides confidence in the current results.

While all of our MJ-smoking participants were classified as chronic, heavy smokers and were required to smoke daily or a minimum of 5 of the last 7 days, none of those included in the present study met diagnostic criteria for MJ dependence, while all met for MJ abuse. Study findings may therefore be specific to individuals who do not endorse the more negative effects of marijuana use (i.e., psychological issues, inability to stop or cut down on use, withdrawal effects) and to those who do not meet for dependence, despite frequent, heavy use. It is of note, however, that none of the MJ-smoking participants in the current investigation were seeking treatment and would therefore not likely have come to the attention of a health care provider, yet they demonstrated significant differences in measures of white matter organization and impulsivity. Taken together with the growing numbers of emerging adults who smoke MJ and the continually decreasing age of MJ onset, these findings support the need and importance of early identification and intervention among individuals who do not report negative effects of MJ use.

In addition, while we did not find any statistically significant differences between the subject groups on any measure of clinical state or demographic variable, it is possible that the groups differed on measures that we did not assess. While some research has suggested that MJ smokers exhibit differences in personality factors relative to nonsmokers (Terracciano et al. 2008; Berg et al. 2011), which could potentially account for some of the heightened impulsivity observed in MJ smokers, the present sample of MJ smokers exhibited no significant differences in personality measures relative to control participants, as assessed by the NEO five-factor inventory (Costa and McCrae 1992), a well-validated personality inventory that provides scores in several domains, including openness, conscientiousness, agreeableness, extraversion, and neuroticism.

Finally, it remains unclear whether the reductions in FA in MJ smokers noted in the present study are the result of demyelination or damage to white matter, delayed or altered brain developmental patterns in MJ smokers, and if they precede or are the result of MJ use. Further, it is unclear if the alterations noted are reversible after extended periods of abstinence. In the current study, MJ smokers were asked to abstain from MJ use for a minimum of only 12 h in order to ensure they were not acutely intoxicated at the time of scanning. Future investigations should examine individuals with extended abstinence in order to determine what impact this has on measures of white matter microstructure. In addition, studies should also focus on former MJ smokers in order to determine the potential recovery of white matter integrity, as extended abstinence from MJ has been shown to result in a “normalization” of brain function (Sneider et al. 2009).