Similar to findings by Lopez-Larson discussed above, the concept of deleterious effects related to early initiation of cannabis has been explored in the neuroimaging literature as well. According to Wilson and colleagues , individuals reporting marijuana use prior to age 17 demonstrated decreased whole brain and cortical gray matter in addition to increased percent white matter volume. Findings also included higher cerebral blood flow in males reporting early initiation of marijuana use. While findings do not necessarily support a clear and consistent pattern of changes in cortical/sub-cortical volume and thickness measurements, as emphasized by Lopez-Larson and colleagues, we can conclude that marijuana may influence the trajectories of appreciable gray matter changes in several ways. The compound may illicit premature tissue development, impose a marijuana-related effect on regressive changes , and alter ongoing myelination of fiber tracts that are impacting gray matter estimates. Functional changes likely affect the mechanics that underlie structural brain changes, and interactions between these processes cannot be ruled out.White matter tissue integrity is believed to be important for efficient cortical connectivity in the developing brain. The literature has shown linear increases in white matter over early development. As the brain becomes increasingly myelinated and fiber bundles mature from infancy to late adolescence, restriction of diffusing water molecules along the principal axis of an axon is commonly observed due to increasingly compact fibers and with more limited intracellular space. Diffusion tensor imaging commonly utilizes two indices of white matter tract coherence to reflect water diffusion in white matter, fractional anisotropy and mean diffusivity , which are thought to help to identify alterations in the health of white matter fibers. Increases in FA and decreases in MD are typically seen in healthy white matter development from young children to early adulthood. In 2006, DeLisi and colleagues published one of the earlier studies to explore the potential for deleterious effects of cannabis on developing white matter.
The authors found higher FA and lower in MD in several tracts in MJ users compared to matched controls; they conclude no evidence of pathological white matter changes despite finding differences between groups. Since this study,greenhouse growing racks findings do suggest some evidence of alterations in white matter integrity in adolescent cannabis users. While DeLisi and colleagues suggest no evidence of pathology per se, subsequent studies have since shown changes in unanticipated directions. While this may not represent a typical pathological process, group differences in either direction may still be reflective of a neural alterations. For instance, increased MD in the prefrontal fiber bundles of the corpus callosum in heavy cannabis using adults who initiated use during adolescence suggest changes in white matter development associated with cannabis use. Ashtari and colleagues found that adolescents with heavy cannabis use enrolled in residential drug treatment had reduced FA and increased MD in cortical association areas such as the temporal-parietal fiber tracts. Recently, in a small sample of adolescents approximately 18 years of age, WM alterations were found in cannabis users compared to controls. Decreased FA in cortical and sub-cortical areas was found in cannabis users compared to controls with no history of substance abuse. In our laboratory, we have found white matter alterations in our abstinent teen marijuana users compared to controls. In two studies published in 2008 and 2009, we found poorer white matter integrity in several association and projection fiber tracts in adolescent cannabis users with concomitant alcohol use. Areas showing between group differences included tracts linked to fronto-parietal circuitry. White matter integrity in several of these regions was linked to neurocognitive performance on measures of attention, working memory, and processing speed; we have also seen white matter linked to emotional functioning and prospective risk taking in our substance users.
To better understand micro-structural differences in tissue integrity among adolescent marijuana users as compared to binge drinkers, we looked at white matter differences between adolescent binge drinkers compared to binge drinkers with histories of heavy marijuana use . While between group differences persisted between marijuana users and controls, surprisingly, teens engaging in binge drinking only looked significantly worse on indices of white matter integrity in several areas as compared to marijuana users, highlighting the need for further research to disentangle the effects of marijuana and alcohol on the developing brain. In general, research points to poorer white matter integrity in adolescent marijuana users compared to non-substance using controls. While white matter findings are subtle in nature, we have observed poorer white matter integrity correlated with poorer neurocognitive functioning in our studies, which underscores the impact that slight alterations in white matter health during this time could have on optimal cognitive functioning. Interestingly, some preliminary evidence supports that marijuana-related toxicity on white matter integrity may be more modest compared to the impact adolescent alcohol use has on the developing brain, although more research in needed in this area.Changes in cognitive performance after acute and longer-term cannabis use are fairly well documented, even if residual effects are suspected to largely resolve. However, less is known on how brain functioning, or neural activation/signaling, may be changed by marijuana use and thereby reflected in declines in neuropsychological performance. Comparisons between blood oxygen dependent signal in adolescent marijuana users and controls in response to cognitive tasks have revealed subtle differences in brain activation patters in marijuana users. Jacobsen and colleagues were the first to pilot an auditory working memory fMRI study comparing marijuana users compared to a tobacco using group and control group. The authors found cannabis users performed the task less accurately and failed to deactivate the right hippocampus across conditions. In another study by the same authors, nicotine withdrawal elicited increased activation across brain regions in the marijuana group, including parietal cortex, superior temporal gyrus, posterior cingulate gyrus, and the right hippocampus. The same effect was not found in the tobacco-only control group suggesting marijuana use may lead to developmental changes masked by nicotine use.We have conducted several BOLD fMRI studies evaluating differences in activation patters between our sample of abstinent marijuana users and matched controls.
In 2007, we found marijuana users to have substantially more activation than non-using peers in response to an inhibitory processing task, particularly in parietal and dorsolateral prefrontal cortices, suggesting additional neural resources required to maintain adequate executive control during response inhibition. In evaluating response patterns to a spatial working memory task, adolescent marijuana users exhibited increased activation in the right parietal lobe along with diminished activation in the right dorsolateral prefrontal cortex to achieve good task performance, which was not observed in controls. In a follow-up investigation using the same spatial working memory task, we evaluated teens with more recent abstinence compared to prolonged abstinence from marijuana, as well as matched controls. Recent users showed greater brain activation in prefrontal cortices, regions needed for working memory processes, and bilateral insula. In response to a third task assessing verbal encoding, marijuana users demonstrated increased encoding-related activation in anterior brain regions as compared to decreased activation in posterior regions, despite no differences in task performance; findings may suggest increased recruitment of neural resources in brain areas sub-serving task-related processing in marijuana using teens. Several recent studies outside of our laboratory have shown similar findings. For example, Jager and colleagues evaluated boys with frequent cannabis use compared to matched controls and found that cannabis users showed excessive activity in prefrontal regions in response to a working memory task, studies from this same research group with young adults have yielded similar, although modest, aberrant findings of the working memory system. In 2010, an investigation comprising chronic marijuana users and matched controls , suggest increased activity in the prefrontal cortex in response to a task requiring executive aspects of attention. Cousijn and colleauges recently found increased activation in heavy cannabis users in response to the Iowa Gambling task during win evaluations in brain areas such as the insula, caudate, and temporal gyrus, which was also positively related to weekly cannabis use; win-related increase in brain activity also predicted increased cannabis use six months later.Lopez-Larson and colleagues found differences in cortico-cerebellar activity in older adolescents with heavy marijuana use. The authors describe decreased activation in response to a bilateral finger-tapping task,vertical hydroponic garden and motor function activation was negatively correlated with total lifetime marijuana use.
Age of onset also continues to play an important role, as early-onset cannabis users demonstrated increased activation in the left superior parietal lobe in response to a verbal working memory challenge , and earlier initiation of use was associated with increased BOLD activity. The majority of findings suggest increased recruitment of neural resources in brain areas sub-serving task-related processing in marijuana using teens. There has been limited research on brain functioning using EEG among adolescent cannabis users. The strength in using EEG is the degree of temporal resolution that is not possible with BOLD imaging. Information on the degree of attentional bias to marijuana cues may provide some indication of brain-based differences in cue-reactivity resulting in heavier use of marijuana among certain teenagers. For instance, one lab based paradigm of cue reactivity found increased skin conductivity among teens diagnosed with cannabis use disorde. Nickerson and colleagues found that among adolescents ages 14–17, P300 response was larger among cannabis users, and response increased in the user group after handling marijuana paraphernalia; findings suggest attentional bias, increased arousal, and possible neural differences that may elucidate discrepancies among teen substance use engagement. The neurovascular effect of marijuana use in adolescence has not been studied extensively. Understanding vascular changes in cerebral blood flow can help us better understand neural signaling and vascular alterations that may be related to changes in neurocognitive functioning and/or changes in neural signaling related to the BOLD signal. Adult studies typically report increased CBF after acute exposure and lower or stabilized CBF after a period of abstinence in heavy users, although this has varied to some degree. To our knowledge, there has only been one study in adolescent blood perfusion in heavy cannabis users. In a recent study in our laboratory utilizing arterial spin labeling , we found that heavy marijuana users assessed pre-and post 28 days of monitored abstinence showed reduced CBF in 4 cortical regions, including the left superior and middle temporal gyri, left insula, left and right medial frontal gyrus, and left supramarginal gyrus at baseline; users showed increased CBF in the right precuneus at baseline, as compared to controls. We did not observe group differences in neurovascular functioning after four weeks of abstinence, suggesting marijuana may influence cerebral blood flow acutely with a possible return to baseline with prolonged abstinence. A study evaluating young adults found that acute THC administration increased blood perfusion in areas important for emotional and cognitive processing, such as the anterior cingulate, frontal cortex, and insula, and reduced perfusion in posterior brain regions. Resting state activity was also altered, as THC increased baseline activity. Very few studies have looked at neurochemical brain changes related to marijuana use in adolescence. Prescott and colleagues found decreases in metabolite concentrations in the anterior cingulate, suggesting poorer underlying neuronal health in adolescent marijuana users, While the exact mechanisms by which cannabis would affect neuronal health is unclear, it is possible that modulation of neurotransmitters such as glutamate and GABAhave adverse consequences on cellular development and neuron integrity; changes in neuronal health is one suggested mechanism which may underlie neuroimaging and neurocognitive findings discussed above.A detailed analysis of the preclinical studies is beyond the scope of this review, however briefly discussing the existing literature is important for translation to human models. Studies also focus on various cannabinoids beside Δ9 -tetrahydrocannabinol , the principal psychoactive component of marijuana; for example increasing attention is being given to cannabidiol, a nonpsychoactive cannabinoid that may have promising therapeutic effects independent of THC. However, this brief summary will focus on models of exposure to the natural compound or cannabinoid agonists, which mimic the structure Δ9 -THC. A great benefit of animal studies is lack of heterogeneity that corresponds with human consumption and substance use reporting. In animals, postnatal days 28–49 correspond with human adolescent development. Studies during this postnatal time period in rats have evaluated both emotional behavior as well as cognitive/behavioral functioning.