The aim of this study was to look at how adolescent binge drinking behavior affects white matter in the context of marijuana use. White matter integrity, indexed by FA, differed between groups in eight clusters located in both association fiber pathways (e.g., fronto-occipital fasciculus, superior longitudinal fasciculus) as well as the corona radiata. These particular association and projection white matter fiber tracts, often implicated in neurocognitive functioning in both adults and children, continue to develop throughout adolescence and are considered important for connecting sensory structures to the frontal lobes [8
Overall, we found that teens reporting histories of binge drinking alone and with concomitant marijuana use displayed lower FA compared to controls. Teens reporting binge drinking behaviors alone had significantly lower FA than controls in all eight clusters, whereas teens reporting both binge drinking and marijuana use had lower FA than controls in only three of the eight clusters: two clusters located in the corona radiata and one cluster in the inferior longitudinal fasciculus. In seven clusters (excluding the right inferior longitudinal fasciculus), teens reporting both marijuana and binge drinking had higher FA values than teens who reported binge drinking only (statistically significant in four of the eight clusters: corona radiata, fronto-occipital fasciculus, middle cerebellar peduncle, superior longitudinal fasciculus).
Interestingly, we observed increasing FA values with more marijuana use in white matter fiber tracts such as the left superior longitudinal fasciculus and the left superior corona radiata. In the superior longitudinal fasciculus, FA values and marijuana use episodes in the past three months were positively related. Also in this region, we found an unexpected positive relationship between lifetime drinking occasions and FA values, even though marijuana use and lifetime drinking frequency were not correlated.
No MD differences between groups were seen in any of the 8 clusters that showed between-group FA differences, or anywhere else in the brain, suggesting the potential mechanism of white matter change in this sample may be alterations in the highly organized fiber structure, as compared to tissue loss or demyelination, although this remains uncertain [7
]. Although the pathological relationship between these diffusion indices (e.g., FA and MD) is not entirely understood due to the complicated geometry of white matter tracts in the brain, correlations between MD and FA may point to contributions to the breakdown in microstructural integrity of white matter (e.g., changes in intra/extra cellular fluid, axonal density, disorganization of fiber structure) [72
]. Our results propose a relationship between both adolescent binge drinking and marijuana use and subtle white matter tissue microstructural abnormalities in varying projection and association fiber pathways (e.g. superior longitudinal fasciculus) that are important for healthy adolescent neural and cognitive development [19
Notably, our results highlight the possible neural consequences of subdiagnostic binge drinking behavior in adolescents, independent of marijuana or other drug use. In support of this hypothesis, animal and human studies have shown that the pathophysiological effects of binge drinking include rate changes in excitatory and inhibitory neurotransmitters in many forebrain structures (e.g., hippocampus, nucleus accumbens), neurochemical metabolite changes, and cell death by inflammatory processes [60
]. Cellular apoptotic death is even suggested to occur with very small doses of alcohol [109
]. Recently, Crews and Nixon (2008) found that ethanol intoxication during binge drinking, as opposed to ethanol withdrawal episodes, may lead to proinflammatory cytokines and increases in oxidative stress. Although the mechanism of white matter change in this sample is complex and not entirely understood, we hope that our findings will build on the current literature exploring the neuropathological consequences of binge drinking on adolescent brain tissue.
While the effects of alcohol use independently on the brain are better understood, the effects of marijuana use remain less clear. Some studies have found evidence of structural and functional brain abnormalities [5
], while other neuroimaging studies report no differences in the brains of heavy marijuana users compared to non-using controls [15
]. In previous studies, our group has found between-group differences in cognition and brain activity in heavy marijuana using adolescents compared to controls [67
]. In this sample, white matter tracts in adolescents who binge drink and use marijuana were more coherent than in adolescents reporting only binge drinking. These findings are unexpected, as recent animal studies have found that rats receiving the psychoactive principal component of marijuana (THC) along with alcohol show an enhanced susceptibility of the developing brain to incur alcohol-related apoptotic neuronal cell death [40
However, our lab has found similar findings looking at macrostructural changes in adolescent hippocampal volumes. We found reduced hippocampal volumes and abnormal asymmetry in adolescent drinkers compared to controls, but did not observe volume or asymmetry abnormalities in teens reporting both
alcohol and marijuana use [59
]. It is possible that marijuana may have some neuroprotective properties in mitigating alcohol-related oxidative stress or excitoxic cell death as suggested in animal models of alcohol-induced neuronal death and cell regeneration [24
]. Although research on the neuroprotective role of cannabinoids is not completely understood, studies have identified several potential neuroprotective molecular mechanisms. For example, activation of cannabinoid receptors may reduce inflammatory activity and excess glutamate neurotransmission that can lead to toxic cell death due to influx of intracellular calcium ion concentrations. Marijuana may also prevent toxicity through anti-oxidative benefits that prevent damage to cellular lipids and proteins, and which may not require cannabinoid-receptor mediated action [18
]. Research on the role of cannabinoids in animal models of binge drinking has found evidence for cannabinoids as a neuroprotectant against binge alcohol toxicity in hippocampal regions when both substances are administered concurrently [36
]. Furthermore, binge alcohol-related modulation of cannabinoid receptors may also contribute to the cellular mechanisms of neuroprotection. Binge alcohol consumption in animals has been found to initially down-regulate CB1 receptors (after 2 days of withdrawal), then up-regulate CB1 receptors later, after 40 days of withdrawal [62
]. Given how widely used cannabis and alcohol are alone and in combination, a greater understanding of their interactive, neuroprotective, and neurotoxic effects is important.
Several limitations in this study should to be noted. Although we did not find differences on demographic variables, these three groups of adolescents could differ on a variable not assessed. Since analyses were not longitudinal, we cannot ascertain if changes resulted from substance use or were preexisting. Lastly, we used a nonprobability sampling approach, and our sample was fairly small precluding the ability to examine continuous relationships between FA, alcohol, and marijuana use within each user group separately. Future studies examining the effects of combined alcohol and marijuana use on microstructural integrity of white matter will need larger samples.
In this study, we found that concomitant binge drinking and marijuana use was not associated with better white matter compared to controls, but higher FA values compared to adolescents reporting only binge drinking. Findings suggest that binge drinking may lead to microscopic disruption of white matter fibers. Although not evaluated in this study, alcohol-related diffusion changes in white matter tissue have been linked with altered cognitive performance in adult samples [73
]. Studies on cognitive and behavioral consequences of binge drinking have found differences in executive functions including decision-making, which may be related to changes in neural circuitry [46
]. Gender effects have even been suggested, with female bingers performing worse on neurocognitive tasks compared to male bingers and controls [98
]. In future studies, we plan to examine how white matter changes in these adolescents over 18 and 36 month follow-up periods as well as how these changes relate to drug use and risk taking behavior.