Does substance use change the brain’s structure, or does brain structure predispose some to substance use?

A study led by researchers from the Indiana University School of Medicine, Washington University in St. Louis, and other institutions has identified neuroanatomical differences in children associated with early substance use initiation.

Early-age substance use is strongly associated with a heightened risk for substance use disorders (SUDs) and other adverse outcomes later in life. Neuroanatomical changes in brain structure have been linked to substance use, especially in youth when the brain is undergoing substantial development.

But are the changes seen in substance user brains primarily a result of the substance use itself, or is it an inherent predisposition in some individuals with certain neuroanatomical variations?

In the study, “Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence,” published in JAMA Network Open, investigators conducted a longitudinal study of complex behavior and biological development from middle childhood to young adulthood, tracking substance use and brain structure.

A total of 11,875 children aged 8.9 to 11 years at baseline were recruited from 22 US research sites. The final analysis included 9,804 from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study (ABCD Study).

Self-reported substance use initiation (alcohol, nicotine, cannabis, or other substances) was recorded alongside baseline magnetic resonance imaging (MRI) scans evaluating brain structures.

Researchers examined 297 imaging-derived phenotypes, including whole brain, cortical and subcortical volumes, thickness, surface area, and sulcal depth. Covariates included age, sex, pubertal status, familial relationships, prenatal substance exposure, and MRI scanner models.

Statistical analyses compared brain structure in participants who initiated substance use before age 15 with those who remained substance-naive. Post hoc analyses excluded baseline substance users to isolate brain structure differences preceding initiation. Multiple testing corrections were applied to validate the findings.

Results suggest that structural brain variability, including larger overall brain volumes and regionally thinner prefrontal cortex, may predispose youth to begin using substances such as alcohol, nicotine, and cannabis before age 15. These structural differences were observed prior to substance use, indicating they reflect a preexisting state, potentially risk factors rather than consequences of substance exposure.

Among participants, 3,460 (35.3%) reported substance use initiation before age 15, with alcohol being the most common (90.2% of cases).

Brain structure differences included:

• Significant associations with thinner cortical regions in the prefrontal cortex, specifically the rostral middle frontal gyrus. Increased cortical thickness in occipital, parietal, and temporal lobes.

• Greater whole brain, cortical, and subcortical volumes were associated with substance use initiation, including larger hippocampal and globus pallidus volumes.

• Cannabis use was uniquely associated with reduced right caudate volume. Post hoc analyses confirmed most findings in substance-naive children, suggesting structural differences preceded substance use.

In an invited commentary, “The Adolescent Brain Cognitive Development Study and How We Think About Addiction,” published in JAMA Network Open, Felix Pichardo and Sylia Wilson with the Institute of Child Development at the University of Minnesota Twin Cities highlight the study’s relevance to rethinking causal assumptions in brain disease models of addiction.

They find the ABCD Study’s large sample size, longitudinal design, and genetically informative components (family study design, nested twin subsamples, and DNA collection) as keys to improving causal inferences about neural risk factors.

Importantly, they suggest that unbiased scientific data provided by studies like this “…have the potential to yield findings that make us reevaluate our current causal assumptions and how we think about addiction.”

The current study aligns well with the findings from another recent study covered by Medical Xpress in which researchers at Washington University in St. Louis found a similar result. In that study, psychosis symptoms were found to precede adolescent cannabis use.

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