The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use

Approximately 10-20% of U.S. adolescents report past-year cannabis use (CU). Although regular CU beginning in adolescence is expected to have a blunting effect on the dopamine system, safety concerns about methods like positron emission tomography have precluded testing this hypothesis in adolescents. However, dopamine neurophysiology can be noninvasively indexed via subcortical tissue iron measured with magnetic resonance imaging (MRI). We examined adolescent CU quantity, frequency, and problems in relation to tissue iron in regions with high dopamine activity, hypothesizing an inverse relationship to reflect the aforementioned blunting effect. Adolescents (n=81) aged 14-17 who reported either fewer than 5 lifetime cannabis episodes (n=47) or more than 11 episodes (n=34), with limited alcohol and nicotine use and no other illicit substance use, completed substance use assessments and an MRI. We calculated the inverse of the normalized T2* measurement (1/nT2*; lower values indicate less tissue iron) from preprocessed resting-state functional scans by assessing relative T2* decay. Tissue iron levels were estimated for the ventral tegmental area (VTA), bilateral thalamus, nucleus accumbens, caudate, putamen, and pallidum using subcortical masks. Lower tissue iron was associated with increased daily concentrate hits and hours high, CU sessions, and cannabis use disorder (CUD) severity in linear mixed models. Post-hoc analyses highlighted the VTA as a key region. Our results align with findings of blunted dopamine neurophysiology associated with CU in adult and animal samples, and have implications for understanding adolescent CUD development. Measuring brain tissue iron offers an innovative, non-invasive method to index dopamine neurophysiology in adolescent CU.