Cannabis is a commonly used psychoactive drug, particularly among adolescents and young adults. 78% of cannabis users are between 12 and 20 years old. This is concerning as cannabis use during adolescence has been linked to long-lasting deficits in executive functioning and impulse control.
The potential association of cannabis use with adolescent development represents a public health problem, especially in areas where recreational cannabis use has been legalized.
The transition from late adolescence to adulthood is characterized by significant brain structural change, most notable in areas with long developmental trajectories and relatively late myelination. Evidence indicates that the adolescent brain may be particularly sensitive to disruptions in normative fluctuations in endocannabinoid signaling, in association with alterations in neurodevelopment and behavior.
Here, the association between cannabis use and brain cortical development was examined. From the IMAGEN sample, adolescents with no prior cannabis use at baseline and with neuroimaging data available at baseline and 5-year follow-up were identified.
First, we examined the extent to which cannabis use was associated with cortical thickness at 5-year follow-up. To assess the temporality of this association, we examined the extent to which cortical thickness at age 14 was modified by cannabis use at 5-year follow-up.
A linear mixed-effects model (MLM) was used to test the extent to which initiation of cannabis use was associated with change in cortical thickness in relation to age (14 to 19 years). Follow-up was conducted to test the extent to which cannabis-related cortical thinning was associated with aspects of impulsive behavior.
We also evaluated the association between cannabis-related cortical thinning map and cannabinoid receptor 1 (CB1) availability using positron emission tomography (PET) (collected from young adults) with the hypothesis that areas showing cannabis-related weight loss would exhibit relatively greater availability of the CB1 receptor.
It was hypothesized that cannabis-related thinning would be most evident in cortical regions that experience the greatest structural change during the developmental window studied.
| Results |
The study evaluated 1,598 MR images from 799 participants. At 5 years of follow-up, a dose-dependent association was evident between cannabis use and cortical thickness, with significant negative associations between consumption and left and right prefrontal cortical thickness.
There were no significant associations between baseline cortical thickness and lifetime cannabis use, suggesting that the neuroanatomical differences observed at 5 years did not precede the onset of use.
MLM analysis revealed a significant time × cannabis interaction as use was associated with accelerated age-related bilateral prefrontal cortical thinning; The results were not altered when controlling for baseline age and time period between controls. The statistical map of this interaction was significantly associated with the CB1 receptor availability map by PET, indicating that the cortical areas thinned with age due to cannabis use partially overlapped with the higher density of CB1 receptors.
The association between age and cortical thickness was also characterized in virgin consumption participants. There was a significant association between time points and cortical thickness, with most cortical areas evidencing age-related thinning. The spatial pattern of cannabis-related cortical thinning was correlated with the statistical map for temporal association, indicating that cannabis-related thinning was greater in cortical regions that evidence more significant age-related thinning.
In all analyses, controlling for socioeconomic status, verbal IQ, and performance IQ did not alter the results. There was no significant interaction between sex and cannabis on cortical thickness. In the longitudinal analysis, the time × cannabis × sex interaction was not significantly associated with cortical thickness, indicating that the association between age-related thinning and cannabis use does not differ between sexes.
Cannabis-related cortical thinning in the right dorsomedial prefrontal cortex accounted for unique variance in attentional impulsivity at 5-year follow-up controlling for sex, site, baseline age, baseline brain volume, pubertal development, verbal IQ, and performance IQ. Follow-up analyzes revealed no associations between cannabis-related weight loss and other psychopathological and neurocognitive measures.
| Discussion |
The results suggest that cannabis use during middle or late adolescence may be associated with altered cortical development, particularly in prefrontal regions rich in CB1 receptors and exhibiting prolonged maturation trajectories. Evidence was found for a dose-dependent association between cannabis use and accelerated cortical thinning over the 5-year period.
The neuroanatomical variations observed with cannabis use were not associated with pre-existing brain structural alterations. Furthermore, the cortical areas in which the transition to cannabis use was associated with accelerated age-related weight loss were, on average, the regions with the highest availability of CB1 receptors.
The analyzes indicate a possible consequence of cortical alteration by cannabis, since thinning of the right dorsomedial prefrontal cortex was associated with attentional impulsivity at the 5-year follow-up.
Numerous studies have evaluated the brain structural correlates of cannabis use in adolescents, although findings have been inconsistent. In general, when comparing adolescent consumers with non-consumers, a reduction in volume and/or surface area of frontal and parietal areas and cortical thickness in frontal regions was observed. However, other studies found evidence of increased volume and/or thickness in temporal and cerebellar regions in consumers, and others revealed no differences.
It has long been postulated that ongoing neurodevelopmental processes during adolescence may lead to increased vulnerability to cannabis exposure and increase the likelihood of long-term associations with cognition and behavior. Animal studies reported long-lasting effects of exposure to tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, such as alteration of social behavior and motivational processes. In humans, adolescent-onset cannabis users exhibit greater problems associated with such use in adulthood than late-onset cannabis users.
The findings of the present study may help elucidate the increased vulnerability to the effects of cannabis use in adolescents. The statistical map of cortical change according to age was significantly correlated with the statistical maps of time × cannabis interaction in relation to cortical thickness at 5 years of follow-up.
These results suggest that cannabis use tended to localize cortical thickness change within areas that were already experiencing a greater degree of age-related modification (from baseline to 5-year follow-up). This finding provides support for the association between cannabis use and ongoing brain maturational processes and provides a possible explanation for the increased vulnerability to unfavorable cognitive outcomes from cannabis use among adolescents.
Most importantly, the imaging findings are consistent with recent animal research on THC exposure and prefrontal cortical maturation , in which exposure disrupted normal neurodevelopmental processes by inducing premature dendritic pruning in early adulthood. The cannabis-related cortical thinning revealed by MRI in this study is considered to be underpinned by the same neurobiological phenomenon.
This study has several strengths . All participants reported not having previously used cannabis, and, for those who transitioned to use, exposure occurred during the same developmental window. Additionally, the number of participants offered greater statistical power to detect more subtle brain structural changes.
Several limitations must also be addressed . The PET data used in this study were collected from a separate sample of young adults, not the participants. Given the invasive nature of PET and its associated risks, it is unethical to collect PET data in minors.
Therefore, it cannot be definitively stated that in this sample the areas exhibiting cannabis-related thinning in MRI analyzes were high in CB1 availability. Additionally, it is possible that participants were not honest about their cannabis use or that their estimates of use were inaccurate. There is also uncertainty regarding the exact neurobiological mechanisms associated with cortical thinning as assessed by MRI.
Research suggests that it could reflect increased myelination of the lower cortical layers rather than synaptic pruning and/or neuronal cell loss; however, this study focused on cortical thickness and did not examine potential cannabis-related outcomes on subcortical structures.
Given the observational nature of the study, it is possible that the association between cortical thinning and cannabis use reflects pre-existing brain maturation trajectories not caused by cannabis use. Therefore, the possibility that pre-existing cognitive and/or behavioral differences are associated with neurological developmental trajectories from adolescence to early adulthood and that cannabis use is not causally related to brain thickness cannot be ruled out.
Conclusions
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