Neuroanatomical Variability Linked to Pediatric Substance Use

Neuroanatomical variability is associated with early substance use initiation, according to a cohort study published in JAMA Network Open.

Researchers analyzed a longitudinal study of pediatric patients aged 9 to 11 to explore the relationship between baseline brain structures and the initiation of alcohol, nicotine, cannabis, or other substance use before age 15.

A total of 9804 patients were included in the study, of whom the mean (SD) baseline age was 9.9 (0.6) years, 52.6% were boys, and 76.1% were White. By the end of the 3-year follow-up, 35.3% of patients had initiated substance use. Among those patients, 44.9% reported prenatal substance exposure, and 51.1% were classified as prepubertal at the study’s start.

Patients who began using substances before age 15 displayed significant neuroanatomical differences when compared to their peers. Notably, they had decreased cortical thickness in prefrontal regions, particularly in the rostral middle frontal gyrus, which showed a negative association with substance use initiation (β=−0.03; 95% CI, −0.02 to −0.05; P =6.99 × 10⁻⁶).

Conversely, these patients displayed greater global brain volumes, including larger whole brain volume (β=0.05; 95% CI, 0.03 to 0.06; P =2.80 × 10⁻⁸), and increased volumes in subcortical structures such as the hippocampus and globus pallidus. Specific to cannabis use, researchers observed a smaller right caudate volume (β=−0.03; 95% CI, −0.01 to −0.05; P =.002).

Post hoc analyses suggested that many of these neuroanatomical differences predated substance use initiation, as they were evident at baseline in substance-naive children who later used substances. This suggests that structural variations in the brain could indicate susceptibility to substance use, rather than merely reflecting its effects.

These results align with neurodevelopmental models that emphasize asynchronous brain maturation during adolescence. Specifically, the earlier development of subcortical regions relative to the delayed maturation of prefrontal areas may increase risk-taking behaviors and vulnerability to substance use. The authors highlighted that this imbalance may impair cognitive control, contributing to early experimentation with substances.

Study limitations include an observational design, a narrow follow-up period, and a lack of analysis on environmental variables.

“Ultimately, a greater understanding of the links between brain structure and substance involvement may uncover predispositional risk factors that provide insight into the early causes of [substance use disorders] and clinically informative mechanisms through which myriad adverse health outcomes associated with substance involvement emerge,” the researchers concluded.

Disclosures: This research was supported by the National Institutes of Health (NIH) and additional federal partners, including grants from various NIH institutes under the ABCD Study.