Increased RD has been related to demyelination in neurodegenerative diseases such as multiple sclerosis,suggestive of a neurotoxic effect with early age of first use of marijuana. These findings taken together, and in line with previous studies,suggest that an earlier age of onset is associated with decreased coherence of white matter. Moreover, these results suggest that marijuana use has an impact on the development of these white matter tracts during adolescence.We then investigated whether the shape of the hippocampus, amygdala, or accumbens was impacted by marijuana use. For the full sample of users, the results are shown in Fig. 4. There was a trend for a significant negative relationship between the number of times used and scalar values in the left amygdala.Participants with a higher number of times used showed more inward deflection in the superficial group of the left amygdala. In the right nucleus accumbens, there was a significant positive relationship between age of first use and shape, such that participants with an earlier age of onset of use showed greater outward deflection.This finding suggests that a later age of first use is related to more outward deflection of the right anterior nucleus accumbens. In the left hippocampus cornu ammonis and posterior hippocampus subiculum, a greater number of times used was associated with greater inward deflection.The effects of the number of times used cannabis grow equipment in the restricted sample closely mirrored those in the full sample. In the left superficial amygdala there was a trend for participants with a higher number of times used to show more inward deflection.Likewise, the same pattern was observed in the left hippocampus cornu ammonis.
For age of first use, however, there was the opposite pattern,albeit in the left posterior nucleus accumbens,suggesting that a later age of first age is associated with a more inward deflection of the left posterior nucleus accumbens. This latter finding is similar to that observed by Gilman et al. who found that more frequent use was associated with an inward deflection of the nucleus accumbens. When comparing users and non-users, significant effects on shape were discovered in the right amygdala and left hippocampus. There were two clusters in the right amygdala, one in the dorsal superficial group and another in the ventral laterobasal group, that showed more outward deflection in users compared to non-users. Similarly, in the left ventral anterior hippocampus,users showed more outward deflection compared to non-users. This region was more ventral and anterior to the cluster in the subiculum that showed a negative association with times used in users. These group results are somewhat surprising, as the correlational analyses within users showed inward deflections in more heavy users. However, the left and right nucleus accumbens also showed opposite patterns of inward and outward deflections with greater use, respectively. Thus, one possibility is that marijuana has differential effects in the left and right hemispheres. Nevertheless, Gilman et al. found more inward deflections for heavy users in both left and right nucleus accumbens and the right amygdala.Despite a trend of de-criminalization and softening societal views, the scientific literature on the effects of marijuana on the brain has not yet reached a consensus. Work with adolescents has consistently shown that heavy marijuana use leads to disruptions in the integrity of white matter.However, work investigating the effects of marijuana on the morphometry of gray matter and subcortical regions has yielded inconsistent findings, with several papers even providing strong evidence that heavy marijuana has no effects on brain morphometry.
The current study took a broad look at this question using a multi-modal neuroimaging approach on data from almost 500 participants reporting varying levels of recreational marijuana use. These data from the HCP include the highest quality neuroimaging data publically available, with almost twice the resolution for structural images,and using state of the art diffusion imaging.This large data-set enabled us to investigate parametric associations between marijuana use and cortical and subcortical brain morphometry and white matter integrity. An advantage of this data-set is that it represents a representative community sample, with great variability in race,ethnicity, gender, education level, mental health symptoms, and drug use.Moreover, such ‘big data’ sets like the HCP are becoming more and more commonplace,and it will be important to mine these data-sets to discover new insights about the functions and organization of the human brain. Importantly, this data set provided information on age of first use providing information on whether or not use occurred during early adolescence. Adolescence is a time of critical brain development for white matter tracts, with white matter volume increasing into young adulthood.Heavy marijuana use during this critical period may impact development,and specifically, a number of frontal and association white matter tracts show decreased white matter integrity with heavy adolescent use.Recently, Becker et al. found that over the course of two years, young adults with an adolescent onset of marijuana use showed reduced longitudinal development of FA in key frontal, central, and parietal white matter tracts. The current findings are largely consistent with those reports. We found that an earlier age of first use was associated with decreased FA and increased RD in long-range tracts including the forceps minor, Superior Longitudinal Fasciculus, and Inferior Longitudinal Fasciculus. Given that the average age of participants in the current study was 29.2, the effects of marijuana on white matter appear to be long lasting, persisting 10–20 years after the first use of marijuana. Future, studies should examine the effects of duration of use on the trajectory of brain development.
With regards to shape, a recent meta-analysis has suggested that the subcortical structure most consistently implicated in showing an effect of marijuana use is the hippocampus.Consistent with that finding, we observed that anterior aspects of the hippocampus showed shape differences due to the number of times marijuana has been used. This finding is interesting as anterior and posterior sub-regions of the hippocampus have dissociable roles in memory, with the anterior portion being involved more in memory encoding and the posterior portion being involved more in memory retrieval ; however, an exploratory analysis revealed no connection between hippocampal or amygdala shape and memory performance in these participants.Gilman et al. used a similar multi-modal approach and found that gray matter density,shape,and volume of the left nucleus accumbens was significantly different for recreational users and controls. More specifically, in users, the left and right accumbens showed a negative relationship between shape and marijuana use frequency, such that the accumbens showed more inward deflections with more frequent recent use, as well as greater volume. However, in an attempt to replicate these findings, Weiland et al. found that the results of Gilman et al. held only when participants were not matched in terms of alcohol use. When matched for alcohol use, marijuana users and controls showed no significant effects in terms of cortical or subcortical morphometry. Moreover, when Weiland et al. examined the effect sizes observed in 11 prior studies, they found a net zero effect for the effects of marijuana on brain morphometry.Notably the results of the current study take into consideration the potentially confounding factors of alcohol and tobacco use as well as gender, age, and years of education. A recent paper using some of the same sample from the HCP examined how genetic vs. environmental factors might contribute to brain volume as a function of marijuana use. However, their analyses suggested that the results for the amygdala are likely driven by shared genetic factors as compared to environmental factors as both marijuana user twins and their non-user twin showed reduced volume compared to concordant non-user twins. While the current study did not directly examine the role of genetics and shared environment in mediating the effects of marijuana on the brain, our analyses accounted for family structure.
When accounting for family structure, we found no effects of marijuana on the amygdala, and a trend for a more inward deflection of the right accumbens, but no accompanying difference in volume. However, the analysis of Pagliaccio et al. was limited in sample size for certain sibships, in particular, monozygotic twins discordant for marijuana use. With the upcoming complete HCP data-set consisting of 1200 participants, it will be important to update the analyses of Pagliaccio and colleagues, as well as adding subcortical shape as a measure, to see if a causal relationship arises with a larger sample .As the current study is not longitudinal but rather cross-sectional, it cannot speak to whether the use of marijuana causes changes in neural structures. Such an analysis will require longitudinal data as is to-be collected by the new national ABCD study funded by NIH. Nonetheless, the current study can provide hints as to potential effects of marijuana use due to its large sample size and because family structure was controlled for in the analyses. In addition, despite the 100-fold increase in the number of marijuana users from most studies and the high-quality of imaging data, the data on marijuana use history from the HCP is relatively sparse. Whereas alcohol and tobacco were assessed in terms of recent and past use, questions of marijuana use were restricted to self-report measures of the age of first use and the number of times used in the lifetime. As such,vertical grow system it was not possible to accurately examine the effects of duration of use or more specifically, the effects of time since last use. As noted in the Materials and methods Section, the age of first use and number of times used data was coarsely coded using relatively arbitrary ranges. In particular, the number of times used score presented widely different categories for participants to select, ranging from 1–5 times used to “more than 1000.” Moreover, no data was available regarding the recency of this use. Additionally, while tobacco and alcohol were controlled for using scores selected to best represent the impact of chronic, co-morbid substance use, it is possible that alternative metrics would change the representation of variance due to these substances.
As it stands, the alcohol and tobacco use scores used in this presented significant co-variance with age of first use and times used, highlighting both the need to control for these factors and the importance of a data-set large enough to separate the effects of each variable. While participants were excluded from the HCP for major psychiatric or neurological illness participants underwent a psychiatric screening as part of the SSAGA, and psychiatric symptoms were assessed with the NIH Toolbox and the Achenbach Adult Self-Report questionnaire.Examining the interactions of psychiatric symptoms and marijuana use was beyond the scope of the current study, but future studies should examine these effects. Previous studies have shown that adolescent marijuana use is co-morbid with a number of psychopathologies including childhood trauma,depression,attention-deficit hyperactivity disorder,and psychosis.Furthermore, the HCP contains information about parental psychopathology. While much of the psychiatric information available in the HCP has less information than a targeted study of psychopathology, there is enough information for future studies to assess multivariate effects of marijuana use variables and co-morbid psychopathology and other substance use. Lastly, while the advanced imaging analyses used in this study provide powerful ways to non-invasively understand the anatomical changes occurring with a brain, they are limited in that they cannot speak to the mechanisms whereby marijuana use might influence brain structure. Specifically, they cannot elucidate the microscopic changes responsible for the more macroscopic GM and WM impacts.For example, while shape changes of the accumbens and hippocampus might reflect inflammation, marijuana has been found to have anti-inflammatory properties.Macroscopic morphological changes could be caused by neuronal loss or changes in cytoarchitecture such as neuronal size, dendritic spine density, dendritic length, or synaptic protein levels.As such, morphometry studies can strongly inform where such changes are occurring, but cannot pinpoint the microscopic causes of these structural changes. It is important to note that the two major components of marijuana, Δ-9-tetrahydrocannabinol and cannabidiol,have opposite effects behaviorally, symptomatically, and in terms of functional activation of all of the regions-of-interest for the current study.With legalization of marijuana comes more accurate assays of THC and CBD concentrations, and thus, future research can and should focus on examining whether THC and CBD have dissociable effects on brain morphometry .