Nature Communications: Developmental Variation in Basal Ganglia Tissue Iron, Neurocognitive Functioning, and Impulsivity Is Associated with Substance Use Trajectories in Youth
Illicit substance use increases dramatically during the teenage years, with only 15% of US 8th graders reporting substance use in a 2024 study, compared to approximately 37% of high school seniors. Neurodevelopmental theories of adolescent substance use propose that a developmental peak in subcortical, dopaminergically mediated reward systems interacts with still-maturing, yet largely accessible, prefrontal cognitive control systems. Heightened reward reactivity can bias decision-making processes, creating a window of vulnerability for elevated substance use.
Investigators including Ashley Parr, PhD (Research Assistant Professor of Psychiatry), Finnegan Calabro, PhD (Research Assistant Professor of Psychiatry and Bioengineering), Duncan Clark, MD, PhD (Professor of Psychiatry and Pharmaceutical Sciences), and Beatriz Luna, PhD (Distinguished Professor of Psychiatry, Bioengineering, Psychology, and Radiology, and Staunton Professor of Pediatrics and Psychiatry), examined how basal ganglia tissue iron (a marker of dopamine-related neurobiology) and neurocognitive functioning relate to substance use patterns from adolescence into adulthood. A cohort of 802 adolescents and young adults from the multi-site National Consortium on Alcohol & Neurodevelopment in Adolescence and Adulthood (NCANDA-A) study was followed for up to nine years, with longitudinal magnetic resonance-based assessments of basal ganglia tissue iron, and repeated behavioral assessments of impulsivity, inhibitory control, and substance use.
The investigators reported findings from the study in Nature Communications. Elevated impulsivity, reduced inhibition, and lower tissue iron were independently associated with greater substance use frequency and use of multiple substances, and with distinct developmental trajectories of substance use. Four trajectory groups include no or low use, youth peaks, adolescent increasing, and adult increasing. The youth peak and adolescent increasing groups showed elevated impulsivity early in adolescence, and the youth peak group additionally exhibited lower tissue iron, suggesting that low dopamine-related neurobiology may drive youth’s propensity toward substance use. However, notably, as individuals in the youth peak group got older, their brain dopamine levels steadily increased and impulsivity decreased, coinciding with an age-related decrease in substance use.
“Our findings suggest that developmental changes in dopamine-related brain systems may help explain why some adolescents are more likely to experiment with substances. For some adolescents, lower dopamine function may increase the drive to seek out highly rewarding or stimulating experiences – including substance use – but as these brain systems mature, many naturally reduce their use over time. This highlights an important distinction: experimentation during adolescence does not inevitably lead to persistent substance use problems. By following youth over nearly a decade, we were able to distinguish adolescents who age out of substance use from those who continue to escalate into adulthood. Understanding these distinct developmental pathways provides a framework for distinguishing normative adolescent experimentation from patterns that signal longer term risk, opening the door for earlier and more targeted intervention and prevention efforts,” said Dr. Parr, corresponding author of the study.
Parr AC, Ojha A, Petrie DJ, Calabro FJ, Tervo-Clemmons B, Foran W, Fitzgerald D, Tapert SF, Nooner K, Thompson W, Goldston DB, Clark D, Luna B.
Nat Commun 17, 4861 (2026). https://doi.org/10.1038/s41467-026-73611-1